WO2023233475A1 - Method for treating dementia - Google Patents
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- WO2023233475A1 WO2023233475A1 PCT/JP2022/021968 JP2022021968W WO2023233475A1 WO 2023233475 A1 WO2023233475 A1 WO 2023233475A1 JP 2022021968 W JP2022021968 W JP 2022021968W WO 2023233475 A1 WO2023233475 A1 WO 2023233475A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61N7/00—Ultrasound therapy
Definitions
- the present invention relates to a method for treating dementia.
- AD Alzheimer's disease
- MCI mild cognitive impairment
- Dementia is a condition in which cognitive function declines due to various causes such as brain diseases and disorders, which interferes with daily life in general.
- AD is the most common type of dementia, accounting for approximately 70% of cases, and causes degeneration of cranial nerves and atrophy of parts of the brain.
- senile plaques are the pathological condition, and cognitive decline progresses in a natural course.
- Amyloid- ⁇ (A ⁇ ) accumulates in the brain before the onset of the disease, and after the onset of the disease, neuronal cell death progresses due to phosphorylation of the tau protein. During this process, memory and thinking ability are slowly lost, and eventually the simple tasks of daily life become difficult. It is said that he will lose his abilities, become bedridden, and die.
- Non-Patent Document 3 Non-Patent Document 3
- DBS-f Fornix
- DBS deep stimulation therapy
- Pivotal studies have not yet been completed for these drugs, so it is difficult to judge their efficacy and safety from the current public information (Patent Documents 1-3).
- Non-Patent Literature 4 Non-Patent Literature 4 It has also been revealed that its mechanism of action is based on a mechanism involving ⁇ 1-integrin or caveolin-1 (Non-Patent Document 5, Figure 1).
- Patent Documents 5 and 6 LIPUS has received wide attention in orthopedics, cerebral infarction areas, neuronal regulation, etc.
- An object of the present invention is to provide a new method for treating dementia that is different from conventional dementia treatments.
- the inventors of the present invention have developed a system that allows patients with mild cognitive impairment (MCI) and mild AD to receive a transducer that spreads from multiple convex transducers under a predetermined treatment program.
- MCI mild cognitive impairment
- AD cognitive impairment
- a method for treating a patient with dementia comprising: Using multiple convex transducers, an ultrasound transducer placed on the convex transducer to transmit unfocused ultrasound energy to the brain, and an ultrasound generator connected to the convex transducer, the convex transmitting unfocused ultrasound energy generated from an ultrasound transducer disposed in a transducer to the patient's brain; The step sequentially irradiates the unfocused ultrasound energy between the plurality of convex transducers, A method of irradiating the unfocused ultrasound energy according to the following treatment program: Treatment program Duration of one irradiation: 1 to 60 minutes Daily treatment: 1 to 4 irradiations per day 1 session: 1 day treatment, 1 to 7 times over 5 to 10 days Number of sessions: 1 session treatment Repeat this continuously every 4 to 16 weeks for 6 or more sessions.
- the present invention by irradiating unfocused ultrasound energy under a predetermined treatment program, it is possible to transmit ultrasound energy to a wide range of brain tissue including the hippocampus and corpus callosum, and to treat patients with dementia. It can suppress the deterioration of cognitive function and treat dementia. Therefore, according to the present invention, it is possible to provide a new method for treating dementia that is different from conventional dementia treatments.
- FIG. 1 shows a schematic diagram of the molecular mechanism of increased expression of eNOS and VEGF associated with LIPUS irradiation, as reported by the present inventors (Non-Patent Document 5, FIG. 1).
- Figure 2 shows a schematic diagram of the proposed mechanism for the effectiveness of LIPUS irradiation in two mouse models of dementia (VaD and AD) reported by the present inventors (Non-Patent Document 9, Figure 2).
- FIG. 3 shows a schematic diagram of an exemplary embodiment of a convex transducer utilized in the method of the present invention.
- FIG. 1 shows a schematic diagram of the molecular mechanism of increased expression of eNOS and VEGF associated with LIPUS irradiation, as reported by the present inventors (Non-Patent Document 5, FIG. 1).
- Figure 2 shows a schematic diagram of the proposed mechanism for the effectiveness of LIPUS irradiation in two mouse models of dementia (VaD and AD) reported by the present inventors (Non-P
- FIG. 4 shows (1) a schematic diagram of ultrasonic energy diffusion in an embodiment of the present invention, and (2) a convex transducer 1 in an embodiment of diffusion in a reverse taper shape that gradually expands in diameter in the radial direction. A side view of each is shown.
- FIG. 5 shows a schematic diagram of an exemplary embodiment of the method according to the invention, in which two convex transducers 1 are placed on the side of the patient's head by means of a headset 5.
- FIG. FIG. 6 shows a schematic diagram of an embodiment in which two convex transducers 1 are placed on the temporal region.
- FIG. 7 is a graph showing the sound pressure dependence of VEGF, FGF2, and eNOS expression (relative values) in HUVEC (in vitro) as reported by the present inventors ((Patent Document 7)).
- FIG. 8 shows the directivity characteristics (hydrophone method) of a convex vibrator.
- FIG. 9 shows a schematic diagram of the ultrasound irradiation site (shaded area) for calculating the temperature rise of the entire tissue.
- FIG. 10 shows the irradiation conditions (A) and treatment program (B) in LIPUS treatment.
- FIG. 11 shows the treatment situation including inclusion and deviation of the Roll-in study (A) and the RCT study (B).
- FIG. 12 is a graph showing the evaluation results of the amount of change from the baseline in ADAS-Jcog total score 72 weeks after the first treatment.
- FIG. 13 is a graph showing the results of the temporal evaluation of the amount of change in ADAS-Jcog total score at 24, 48, and 72 weeks after the initial treatment.
- FIG. 14 is a graph showing the evaluation results of the proportion of ADAS-Jcog responders at 24, 48, and 72 weeks after the initial treatment.
- FIG. 15 is a graph showing the results of the temporal evaluation of the amount of change in the CDR sum of boxes at 24, 48, and 72 weeks after the initial treatment.
- dementia includes mild Alzheimer's type dementia or mild cognitive impairment, and is preferably mild Alzheimer's type dementia or mild cognitive impairment derived from Alzheimer's type dementia.
- the dementia of the present invention may include cerebrovascular dementia.
- Dementia patients to be treated in the present invention include mammals suffering from and/or at risk of suffering from dementia, preferably humans.
- Dementia patients to be treated in the present invention are diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) by the American Psychiatric Association and/or the National Institute on Aging and Alzheimer's Association (NIA-AA). Can be selected based on criteria.
- the dementia patient to be treated in the present invention is a patient who meets one or more of the following criteria: ⁇ Patients who meet the diagnostic criteria for mild Alzheimer's dementia or mild cognitive impairment in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) by the American Psychiatric Association; ⁇ Patients who meet the U.S.
- NIA-AA National Institute on Aging and Alzheimer's Association
- treatment of dementia refers to complete cure or cure of dementia, or temporary or permanent disappearance, reduction, alleviation, or progression (worsening/increasing severity) of some or all symptoms. It means the prevention or reduction (remission) of
- “treatment” of dementia in the present invention includes maintaining or suppressing deterioration of cognitive function of a patient with dementia, or improving cognitive function.
- the effectiveness of dementia treatment can be evaluated using methods conventionally used for dementia testing, such as ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale), Examples include, but are not limited to, ADAS-Jcog and CDR sum of boxes. These methods can score the severity of cognitive function or dementia, and based on changes in the score over the course of treatment, maintenance of cognitive function, suppression of deterioration, or improvement of cognitive function can be evaluated. It is possible to confirm the effectiveness of dementia treatment.
- ADAS-cog Alzheimer's Disease Assessment Scale-cognitive subscale
- the present invention relates to a method for treating a patient with dementia, the method comprising a plurality of convex transducers and an ultrasound transducer disposed on the convex transducer for transmitting unfocused ultrasound energy to the brain. and transmitting unfocused ultrasound energy generated from an ultrasound transducer disposed on the convex transducer to the patient's brain using an ultrasound generator connected to the convex transducer.
- the step is characterized in that the unfocused ultrasound energy is sequentially irradiated between the plurality of convex transducers.
- the irradiation of the unfocused ultrasound energy is performed according to the following treatment program: Treatment program Duration of one irradiation: 1 to 60 minutes Daily treatment: 1 to 4 irradiations per day 1 session: 1 day treatment, 1 to 7 times over 5 to 10 days Number of sessions: 1 session treatment Repeat this continuously every 4 to 16 weeks for 6 or more sessions.
- FIG. 3 shows a schematic diagram of an embodiment of a convex transducer used in the method of the present invention.
- the convex transducer 1 is connected to an ultrasound generator (not shown) via a cable section 2 having a connector section 3 .
- An ultrasound transducer 4 is arranged in the convex transducer to transmit unfocused ultrasound energy to the brain.
- the material of the ultrasonic transducer is not particularly limited as long as it can generate the above-mentioned unfocused ultrasonic energy, but examples include resins (noryl resin, polyacetal, ionomer resin, urethane resin, etc.), metals ( copper alloys, etc.).
- the size of the portion of the convex transducer that generates ultrasonic waves is not particularly limited, but for example, if the portion that generates ultrasonic waves has a substantially circular shape, the diameter is 1.0 to 6 mm. 0 cm is preferable, 2.0 to 5.0 cm is more preferable, and even more preferably 3.0 to 4.8 cm.
- the shape of the part of the transducer that generates ultrasonic waves is not particularly limited, and may be approximately circular, approximately elliptical, polygonal (triangle, quadrilateral (square, rectangle, parallelogram, trapezoid, etc.), pentagon, hexagon, etc.). , heptagon, octagon, etc.) can be designed as appropriate. Further, its dimensions can be appropriately set, for example, to correspond to the dimensions described above for the approximately circular shape so that the ultrasound waves are transmitted to a wider area of the brain.
- a single ultrasonic transducer 4 is arranged for one convex transducer 1, as shown in FIG. Electricity is transmitted from the ultrasonic generator to the ultrasonic vibrator 4 via the cable portion 2, and a voltage is applied to the ultrasonic vibrator 4, thereby causing the ultrasonic vibrator 4 to vibrate.
- the vibration frequency, time, timing, etc. of the ultrasonic transducer 4 are controlled by the ultrasonic generator. Further, by switching the control signals from the ultrasonic generator, the same ultrasonic transducer 4 can be made to function as an ultrasonic receiving element.
- An embodiment including such a receiving element is preferable because it is possible to monitor whether the intensity of the ultrasound transmitted from the convex transducer and transmitted through the brain is within a predetermined range. Note that it is also possible to receive and use its own transmitted ultrasonic waves.
- the ultrasonic irradiation surface of one ultrasonic transducer has a convex curved shape so that the ultrasonic waves advance in a non-focused direction, or by arranging a plurality of ultrasonic transducers in a convex curved shape, Focused ultrasound energy can be efficiently transmitted to the brain, preferably to the whole brain, and as a result, the expression of eNOS is enhanced, and the production of A ⁇ and A ⁇ precursor protein (Amyloid precursor protein, APP) is suppressed.
- Dementia can be treated by regenerating nerves through angiogenesis, increasing the expression of neurotrophic factors, and suppressing phosphorylation of tau protein.
- unfocused ultrasonic energy refers to ultrasonic energy that is diffused without being focused on one point or line.
- the unfocused ultrasound energy is diffused in a reverse taper shape that gradually expands in diameter in the radial direction. It is preferable that the angle at which the inclined surface of the inverted tapered unfocused ultrasonic energy expanding in diameter spreads is 50° to 100°, more preferably 60° to 90°.
- the ultrasonic energy is diffused in a substantially conical shape (the bottom portion may be a curved surface) as shown in FIG. 4(1).
- FIG. 4(2) shows a side view of the convex transducer 1 in an embodiment in which the convex transducer 1 is diffused in an inverted tapered shape whose diameter gradually expands in the radial direction.
- the angle at which the inclined surface of the inverted tapered unfocused ultrasonic energy expands means ⁇ in FIG. 4(2).
- the method is performed with a plurality of (two in FIG. 5) convex transducers 1 placed against the patient's head.
- the location where the convex transducer 1 is applied is not particularly limited, but it is preferably applied to the temporal region (temple) because the skull is relatively thin and it is easy to transmit ultrasound to the brain.
- the convex transducer 1 is attached to a headset 5, and by wearing this headset, the patient can place two convex transducers on the side of his head.
- the patient's posture while undergoing treatment may be a sitting position or a supine position.
- the convex transducer placed in the temporal region spreads unfocused ultrasound energy in an inversely tapered manner, thereby transmitting a large portion of the brain, for example, at least a portion including the hippocampus and corpus callosum, typically Specifically, it is preferable because it can transmit ultrasound energy to the entire brain (Fig. 6).
- the ultrasound generating portion of the convex transducer 1 and/or the convex transducer You may also apply an appropriate gel (also called echo gel, echo jelly, etc.) to the part of the head that is to be applied.
- ultrasound energy can be transmitted to a wider range of the brain.
- ultrasound energy irradiated from multiple locations is transmitted redundantly into the brain, and as a result, excessive ultrasound energy is transmitted into the brain.
- unfocused ultrasound energy is sequentially irradiated between multiple convex transducers.
- "sequentially irradiating unfocused ultrasound energy between a plurality of convex transducers” means to first generate ultrasonic waves with a certain convex transducer among the plurality of convex transducers, and then , the other convex transducer does not generate ultrasonic waves, then another convex transducer generates ultrasonic waves, while the other convex transducers do not generate ultrasonic waves, and so on.
- multiple convex transducers only one convex transducer is generating ultrasonic waves at the same time; in other words, two or more convex transducers do not generate ultrasonic waves at the same time. .
- the ultrasound generated from the convex transducer passes through the skull, is transmitted to the brain, and is reflected by the skull on the opposite side to where the convex transducer is placed. Transmit again in the direction of. Then, the reflected ultrasonic waves are reflected again by the skull on the side where the convex transducer is placed and transmitted. During this time, the ultrasound waves are attenuated as they propagate through the brain and reflect off the skull. In this way, the ultrasound generated by the convex transducer travels back and forth within the brain multiple times, attenuating each time it reflects off the skull.
- the emitted wave or reflected wave of unfocused ultrasonic energy generated from a certain convex transducer is attenuated. It is preferable to leave intervals between the generation of ultrasound waves from the plurality of convex transducers so that excessive ultrasound stimulation does not occur even if the unfocused ultrasound energy is overlapped with the unfocused ultrasound energy generated from the next convex transducer.
- the interval between unfocused ultrasound energy irradiation by a plurality of convex transducers can be expressed as a pulse repetition time (PRT), and PRT is 0.6 to 1 It is preferable to set the time appropriately within a range of .8 milliseconds, and more preferably 1.28 milliseconds.
- PRT pulse repetition time
- the irradiated ultrasound waves are attenuated by reciprocating within the skull as described above (preferably to about 1/100) before the next unfocused ultrasound energy irradiation. (attenuated up to 100%), and excessive ultrasound stimulation due to duplication of ultrasound energy in the brain can be avoided or reduced.
- the interval between unfocused ultrasonic energy irradiations means starting ultrasonic irradiation from one convex transducer, stopping ultrasonic irradiation from that convex transducer, and then When performing irradiation such as starting ultrasonic irradiation from one convex transducer, stopping ultrasonic irradiation from the next convex transducer, etc., from the above purpose, if It means the time from the start of irradiation to the start of ultrasound irradiation with the next convex transducer.
- the irradiation of unfocused ultrasonic energy by the convex transducer is performed appropriately within the range where the amplitude (sound pressure) of the irradiated ultrasonic wave directly below the element (ultrasonic transducer) is 0.1 to 1.5 MPa. It is possible to set it to be preferably 0.3 to 1.3 MPa, more preferably 1.3 MPa. By setting the sound pressure directly below the element within this range, gentle LIPUS stimulation with a sound pressure acting on the tissue of 0.05 to 0.5 MPa can promote the expression of eNOS, etc., and obtain therapeutic effectiveness. (Figure 7: Patent Document 7).
- the directivity characteristics of the vibrator of the convex transducer are as shown in FIG. 8, for example, as a reference measurement value (sound pressure) measured by the hydrophone method, with the highest energy directly below the element.
- the ultrasonic transmission frequency can be appropriately set in the range of 0.1 to 0.8 MHz, and is preferably 0.5 MHz.
- the irradiated ultrasonic wave is a discontinuous wave, and the number of cycles thereof can be appropriately set in the range of 16 to 34 cycles per pulse, and is preferably 32 cycles.
- the number of cycles of ultrasound refers to the number of cycles within the width (also referred to as pulse width in this specification) from the start of ultrasound irradiation to the end of ultrasound irradiation.
- the intensity of the ultrasonic waves can be adjusted by ISPPA, ISPTA, etc.
- ISPPA indicates the average intensity within the pulse width.
- ISPTA indicates the average intensity within a repetition period.
- the ISPTA of the irradiated ultrasound is not particularly limited, but can be set as appropriate in the range of, for example, 720 mW/cm 2 or less, preferably 100 to 500 mW/cm 2 from the viewpoint of promoting angiogenesis, neuron increase, etc. through gentle ultrasound stimulation. , more preferably 250 mW/cm 2 .
- the ISPTA is expressed as the sum of the ISPTA of the irradiated ultrasound waves of each convex transducer.
- the pulse repetition frequency (PRF) of the irradiated ultrasound wave is the reciprocal of PRT, so it can be appropriately set in the range of 556 to 1667 Hz, and is preferably 781 Hz.
- the duty ratio (Duty Cycle) of the irradiated ultrasound is uniquely determined by the frequency, number of cycles, and PRT, so it is not particularly specified, but is preferably 1 to 30%.
- the duty ratio indicates the ratio of the ultrasonic irradiation time in one cycle of irradiating ultrasonic waves for a certain period of time and stopping the ultrasonic irradiation for a certain period of time.
- it shows the ratio of the ultrasonic irradiation time to [ultrasonic irradiation time + irradiation pause time] during one cycle.
- the duty ratio is expressed as the sum of the duty ratios of the irradiated ultrasonic waves of each convex transducer.
- the ultrasound generated from the convex transducer is significantly attenuated when passing through the skull. Furthermore, it is known that the degree of attenuation changes depending on the thickness of the skull through which ultrasound waves pass (Patent Document 7). Therefore, it is also preferable to calculate an appropriate estimated output value based on the numerical value of the skull thickness based on a head CT image taken at the time of diagnosis of dementia, and transmit it as therapeutic ultrasound.
- the treatment time for irradiation with unfocused ultrasound energy is not particularly limited as long as the unfocused ultrasound energy generated from the ultrasound transducer can be transmitted to the patient's brain. However, it can be determined as appropriate depending on factors such as the patient's symptoms and the intensity of ultrasound, and the irradiation time per treatment is preferably in the range of 1 to 60 minutes, more preferably 15 to 25 minutes. The time can be determined as appropriate, particularly preferably 20 minutes.
- the number of irradiations with unfocused ultrasound energy per day can be performed multiple times, and is not particularly limited; It can be set appropriately in the range of 4 times, preferably 2 to 3 times, and more preferably 3 times.
- Each session can be carried out at appropriate intervals, and although not particularly limited, it is preferable to carry out the sessions at intervals of at least 5 minutes or more.
- the frequency with which the above-mentioned "one-day treatment” is performed is not particularly limited, and can be determined as appropriate depending on factors such as the patient's symptoms and the intensity of ultrasound, and is preferably for 5 to 10 days, preferably 5 to 10 days.
- the number of times can be determined as appropriate within the range of 8 days, more preferably 5 days, preferably 1 to 7 times, and more preferably 2 to 3 times, and these times may be set every other day. More preferably, it is set to .
- performing the one-day treatment at the frequency described above can be considered a "1 session" treatment.
- the number of sessions is not particularly limited and can be determined as appropriate depending on factors such as the patient's symptoms and the intensity of ultrasound, but is preferably 6 or more sessions, more preferably 6 to 9 sessions. Yes, and it can be continued as long as no adverse events occur.
- the interval between each session is not particularly limited, and can be determined as appropriate depending on factors such as the patient's symptoms and the intensity of ultrasound, and is preferably determined at an interval of one session every 4 to 16 weeks. more preferably one session every 8 to 12 weeks.
- the present inventors have confirmed that the time required for the effect of LIPUS irradiation to occur is 3 to 24 hours for mRNA (RT-PCR), 1 week for protein expression (Western), and 4 weeks for tissue. (Non-patent Documents 4, 5, 9), assuming that the next session will be performed after the tissue change after LIPUS irradiation, it is desirable to have at least 4 weeks between each session, and 6 to 6 sessions with an 8 to 12 week interval. It is more preferable to conduct more than one session.
- the connection between the convex transducer and the ultrasonic generator may be wired as shown in FIGS. 3 and 5, or may be wireless.
- the number of convex transducers although the embodiment using two convex transducers has been described, three or more convex transducers may be used.
- two convex transducers can be placed on both sides of the head (temples), and a separate ultrasonic probe can be placed on the boundary between the occipital region and the nuchal region (foramen magnum) to irradiate ultrasound.
- Example 1 Simulation of tissue temperature increase during LIPUS treatment The temperature increase in the entire brain tissue due to ultrasound irradiation is thought to reach a steady state in a few minutes because there is perfusion in the entire brain tissue.
- the temperature rise in the worst case is smaller than the diurnal fluctuation of body temperature (approximately 1°C), and the irradiation conditions of the present invention are considered safe. It will be done.
- Irradiation conditions Transmission frequency: 0.5MHz Sound pressure directly below the element: 1.3 MPa Number of cycles per pulse (wave number): 32 cycle PRT: 1.28ms Ultrasonic intensity (ISPTA): 250mW/ cm2
- a diagnosis of early stages of AD (MCI due to AD and mild AD) must meet the diagnostic criteria for mild Alzheimer's dementia or mild cognitive impairment according to DSM-5 at the time of consent acquisition, and meet the NIA/AA diagnostic criteria.
- Patients were considered to be ⁇ probable Alzheimer's disease'' or ⁇ MCI due to Alzheimer's disease.'' Patients with a CDR (Clinical Dementia Rating global score) of 0.5 to 1.0 at screening and an MMSE-J (Japanese version of Mini Mental State Examination) score of >20 at screening were also included.
- CDR Cosmetic Dementia Rating global score
- MMSE-J Japanese version of Mini Mental State Examination
- the main exclusion criteria are as follows. (1) Inability to undergo LIPUS treatment or brain MRI examination, (2) Patients with impaired consciousness with a GCS (Glasgow Coma Scale) score of 12 points or less at the time of enrollment, (3) Symptomatic brain disease within 12 weeks. Infarction or cerebral hemorrhage; (4) patients with 4 or more microbleeds detected on head MRI at the time of enrollment; (5) patients with severe mental illness. Patients of both sexes who met the inclusion criteria and had no exclusion criteria were enrolled in the study between the ages of 50 and 90.
- GCS Garnier Coma Scale
- LIPUS treatment was performed at a facility at Tohoku University Hospital, by a doctor familiar with LIPUS treatment equipment. As shown in Figure 5, LIPUS irradiated the entire brain using convex transducers fixed to both temporal bones using a headset. LIPUS treatment was performed according to the following treatment protocol.
- Treatment protocol ( Figure 10(B): One day treatment: One irradiation time: 20 minutes ⁇ 1 minute, three times with an interval of 5 minutes or more each time.
- 1 session (LIPUS x 3): 1 day treatment was performed 3 times a week, every other day. Number of sessions: 1 session was conducted every 12 weeks for 6 sessions (weeks 0, 12, 24, 36, 48, and 60).
- the frequency (0.5MHz), number of cycles (32), and pulse repetition frequency (PRF) (781Hz) were fixed.
- PRF pulse repetition frequency
- the LIPUS frequency was changed from 1.875MHz in mice to 0.5MHz in humans to reduce the attenuation of ultrasound transmission due to differences in temporal bone thickness.
- patients were followed for 12 weeks.
- patients were randomly divided into two groups and received either LIPUS or placebo treatment for 6 sessions over 18 months, spaced 3 months apart in an outpatient setting (Figure 10).
- the efficacy endpoint was the usability of the LIPUS treatment device in the roll-in study.
- the primary efficacy endpoint was change in ADAS-J cog total score 72 weeks after initial treatment.
- Secondary efficacy endpoints include change in ADAS-J cog total score at weeks 24 and 48 after initial treatment, proportion of ADAS-J cog responders at weeks 24, 48, and 72 after initial treatment, and This included the amount of change in CDR sum of boxes at weeks 24, 48, and 72.
- Responders to LIPUS treatment were defined as patients whose ADAS-Jcog total did not increase (no worsening or no improvement from baseline). Improvements in ADAS-Jcog scores from baseline of 0 points or more, 4 or more points, 7 or more points, and 10 or more points were presented as counts and percentages. A p value ⁇ 0.05 was considered statistically significant.
- ADAS-Jcog Stratified analysis The results of stratified analysis of ADAS-Jcog responders, although only a small number of cases, are as follows.
- Safety evaluation (1) Safety evaluation items 1) Events that occur between the initial study treatment and the end of the observation period for which a causal relationship to the study device cannot be ruled out (headache, dizziness, nausea/vomiting, insomnia, light-headedness, 2) Frequency of head MRI (intracranial hemorrhage, cerebral edema, organic physical disorder, presence or absence of cerebral infarction) 3) Adverse events 4) Malfunctions
- the irradiation conditions and treatment program for unfocused ultrasound energy using a convex transducer according to the present invention can be used in addition to existing dementia treatment drugs as "disease-modifying therapy.” , it was suggested that it may be effective for early AD.
- the results of the primary endpoint suggest that the clinical trial method of the present invention may be able to suppress the deterioration of cognitive function more by the amount of change in ADAS-J cog total score when treated with 6 or more sessions, even when compared to the treatment results with Aducanumab. Therefore, sufficient efficacy and significant differences can be expected by conducting a confirmatory trial with an increased number of patients.
- the present invention which can provide a new method for treating dementia that is different from conventional drug treatments, is extremely useful.
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Abstract
The present invention addresses the problem of providing a novel method for treating dementia which is different from conventional dementia treatments. The present invention pertains to a method for treating a dementia patient which includes a step for transmitting non-converging ultrasonic energy, which is generated from an ultrasonic vibrator positioned on a convex transducer, to the brain of the patient by using a plurality of convex transducers, an ultrasonic vibrator which transmits non-converging ultrasonic energy to a brain and is positioned on the convex transducers, and an ultrasonic wave generation device which is connected to the convex transducers, wherein said step involves sequentially emitting the non-converging ultrasonic energy between the plurality of convex transducers, and performing the non-converging ultrasonic energy emission according to a prescribed treatment program.
Description
本発明は、認知症を治療するための方法に関する。
The present invention relates to a method for treating dementia.
高齢化に伴い、アルツハイマー病（アルツハイマー型認知症、以降「ＡＤ」と略する）の有病率は急速に増加している。日本国内のＡＤ患者数は、２０１２年に４６２万人と推計されており、２０２５年には６７５万人に増加すると見込まれている（非特許文献１）。また、世界ではＡＤ患者数は、２０１９年に５，５００万人、２０３０年には７，８００万人にのぼると推測されている（非特許文献２）。軽度ＡＤはＡＤ患者のうち、３６．６％と言われているため２０２５年は約２４７万人と予測される。一方、認知症予備軍の軽度認知障害（ＭＣＩ）は２０１２年に約４００万人と推定されており、ＡＤ患者と同程度に増加した場合、２０２５年には約５８４万人に増加すると予測される。
As the population ages, the prevalence of Alzheimer's disease (Alzheimer's disease, hereinafter abbreviated as "AD") is rapidly increasing. The number of AD patients in Japan is estimated to be 4.62 million in 2012, and is expected to increase to 6.75 million in 2025 (Non-Patent Document 1). Furthermore, it is estimated that the number of AD patients in the world will reach 55 million in 2019 and 78 million in 2030 (Non-Patent Document 2). Mild AD is said to account for 36.6% of AD patients, and is expected to number around 2.47 million in 2025. On the other hand, the number of people with mild cognitive impairment (MCI), who are at risk for dementia, is estimated to be approximately 4 million in 2012, and if this number increases at the same rate as AD patients, it is predicted that this number will increase to approximately 5.84 million in 2025. Ru.
認知症は、脳の病気や障害など様々な原因により、認知機能が低下し、日常生活全般に支障が出てくる状態をいう。ＡＤは、認知症の中で最も多く、約７０％を占め、脳神経が変性して脳の一部が萎縮していく。ＡＤでは、老人斑を病態とし、認知機能低下がナチュラルコースで進行していく。発症前から脳内にアミロイドβ（Ａβ）が蓄積し、発症後はタウ蛋白質のリン酸化により神経細胞死が進み、この過程で記憶や思考能力をゆっくり失い、最終的に日常生活の単純な作業能力も失い、寝たきりになり死に至ると言われている。ＡＤに対して有効で安全な治療法はまだ開発されていない。症状改善薬として、ドネペジル、メマンチン、ガランタミン、リバスチグミンの４種類の医薬品が提供されているが症状改善効果とＡＤ進行抑制は限定的である。２０２１年６月８日にＦＤＡが疾患修飾薬として、アデュカヌマブ（バイオジェン／エーザイ）を、脳内のＡβプラークを減少させＡＤ病理に作用する初のＡＤ治療薬として迅速承認したが、脳内浮腫等の安全性や、有効性と医療経済性のバランスが懸念され、普及は限定的と予想されている。
Dementia is a condition in which cognitive function declines due to various causes such as brain diseases and disorders, which interferes with daily life in general. AD is the most common type of dementia, accounting for approximately 70% of cases, and causes degeneration of cranial nerves and atrophy of parts of the brain. In AD, senile plaques are the pathological condition, and cognitive decline progresses in a natural course. Amyloid-β (Aβ) accumulates in the brain before the onset of the disease, and after the onset of the disease, neuronal cell death progresses due to phosphorylation of the tau protein. During this process, memory and thinking ability are slowly lost, and eventually the simple tasks of daily life become difficult. It is said that he will lose his abilities, become bedridden, and die. Effective and safe treatments for AD have not yet been developed. Four types of drugs, donepezil, memantine, galantamine, and rivastigmine, have been provided as symptom-improving drugs, but their effectiveness in improving symptoms and inhibiting the progression of AD are limited. On June 8, 2021, the FDA granted accelerated approval for aducanumab (Biogen/Eisai) as a disease-modifying drug, the first AD treatment that reduces Aβ plaques in the brain and acts on AD pathology. It is expected that widespread use will be limited due to concerns about safety and the balance between effectiveness and medical economics.
ＡＤ治療にはこれまで数多くの医薬品での開発が行われてきたが、副作用やBlood-Brain Barrier（ＢＢＢ、血液脳関門）の課題の克服は容易でなく、これまでに百以上の治験がドロップし、治療法として確立させることの難しい状況が続いている（非特許文献３）。
Many drugs have been developed to treat AD, but overcoming side effects and issues with the Blood-Brain Barrier (BBB) has not been easy, and more than 100 clinical trials have failed so far. However, it continues to be difficult to establish this as a treatment method (Non-Patent Document 3).
一方、認知症治療を目指す医療機器は医薬に比較すると少ないが、NeuroEM Therapeutics社の電磁気を用いた経頭蓋電磁気療法の「MemorEMTM」、Cognito Therapeutics社のGamma frequency neuromodulation「GammaSense」、Functional Neuromodulation社の脳深部刺激療法（ＤＢＳ：インプラントにより電気的または磁気的刺激を継続的に送り込むことによって症状の改善を図る治療法）であるFornix (DBS-f)の３例が挙げられる。これらはPivotal Studyが未了のため、現在の公開情報から有効性と安全性について判断することは難しい（特許文献１－３）。
On the other hand, medical devices aimed at treating dementia are rare compared to pharmaceuticals, but include NeuroEM Therapeutics' "MemorEMTM" transcranial electromagnetic therapy using electromagnetism, Cognito Therapeutics' Gamma frequency neuromodulation "GammaSense", and Functional Neuromodulation's brain Three examples include Fornix (DBS-f), which is a deep stimulation therapy (DBS: a treatment that aims to improve symptoms by continuously sending electrical or magnetic stimulation through an implant). Pivotal studies have not yet been completed for these drugs, so it is difficult to judge their efficacy and safety from the current public information (Patent Documents 1-3).
従って、現代社会はＡＤ治療のための新しい有効で安全な治療法を切望している。
Therefore, modern society is in desperate need of new effective and safe treatments for AD treatment.
本発明者らは以前に、動物モデルにおいて、低出力パルス波超音波（Low-Intensity Pulsed Ultrasound:ＬＩＰＵＳ）により、病態特異的にｅＮＯＳ（endothelial nitric oxide synthase）、ＶＥＧＦ（vascular endothelial growth factor）、ｂＦＧＦ（basic fibroblast growth factor）の発現が亢進し、血管新生や慢性炎症の抑制により、慢性虚血性心疾患等に対して、有効で安全に治療法になりうることを発見し報告している（特許文献４、非特許文献４）。また、その作用機序が、β１－インテグリンまたはカベオリン－１を含む機序によることも明らかにしている（非特許文献５、図１）。
The present inventors have previously demonstrated that eNOS (endothelial nitric oxide synthase), VEGF (vascular endothelial growth factor), and bFGF were detected in animal models using low-intensity pulsed ultrasound (LIPUS). We have discovered and reported that by increasing the expression of basic fibroblast growth factor (basic fibroblast growth factor) and suppressing angiogenesis and chronic inflammation, it can be an effective and safe treatment for chronic ischemic heart disease, etc. (patented) Literature 4, Non-Patent Literature 4). It has also been revealed that its mechanism of action is based on a mechanism involving β1-integrin or caveolin-1 (Non-Patent Document 5, Figure 1).
ＬＩＰＵＳは近年、整形外科、脳梗塞領域や神経細胞の調節等で広く注目されており（特許文献５、６）、骨折治療に関しては既に臨床応用されている。
In recent years, LIPUS has received wide attention in orthopedics, cerebral infarction areas, neuronal regulation, etc. (Patent Documents 5 and 6), and has already been clinically applied in the treatment of fractures.
Katusicらは一酸化窒素（ＮＯ）の利用性低下を伴う内皮機能障害が、ＡＤと関連していることを示唆している。また、Iadecolaは、ＡＤに対するｅＮＯＳセラピーの可能性を示唆している（非特許文献６－８）。
Katusic et al. suggest that endothelial dysfunction accompanied by decreased availability of nitric oxide (NO) is associated with AD. Furthermore, Iadecola suggests the possibility of eNOS therapy for AD (Non-Patent Documents 6-8).
本発明者らは、ＬＩＰＵＳによるｅＮＯＳ発現亢進を通じたＡＤ治療への有効性を検証するため、ＡＤモデルマウス（5xFAD mice）を用いたＬＩＰＵＳによる非臨床試験において、ＬＩＰＵＳ照射群において、ｅＮＯＳ発現が亢進し、Ａβ－４２および老人班が減少し、認知機能低下が抑制されることを報告している（特許文献７、非特許文献９、図２）。ＬＩＰＵＳ治療はＢＢＢが障害にならず、脳全体に広範囲に存在する病態（Ａβ等）を低侵襲に治療する手段として期待されるが、ＡＤ患者を用いて有効性と安全性を検証した報告はない。
In order to verify the effectiveness of LIPUS in AD treatment through increased eNOS expression, the present inventors conducted a non-clinical study using LIPUS using AD model mice (5xFAD mice), and found that eNOS expression was increased in the LIPUS irradiated group. However, it has been reported that Aβ-42 and senile plaques are reduced, and cognitive function decline is suppressed (Patent Document 7, Non-Patent Document 9, Figure 2). LIPUS treatment does not interfere with the BBB and is expected to be a minimally invasive means of treating pathological conditions (Aβ, etc.) that exist widely throughout the brain, but there are no reports that have verified its effectiveness and safety using AD patients. do not have.
本発明は、従来の認知症治療等とは異なる新たな認知症の治療方法を提供することを課題とする。
An object of the present invention is to provide a new method for treating dementia that is different from conventional dementia treatments.
本発明者らは、上記課題を解決すべく鋭意検討した結果、軽度認知障害（Mild Cognitive Impairment:ＭＣＩ）及び軽度ＡＤ患者に、所定の治療プログラムの下、複数の凸型トランスデューサーから広がるように照射される非集束超音波エネルギーを脳の広い範囲に伝達させることにより、当該患者の認知機能の悪化を抑制することができ、認知症を治療し得ることを見出した。
As a result of intensive studies to solve the above problems, the inventors of the present invention have developed a system that allows patients with mild cognitive impairment (MCI) and mild AD to receive a transducer that spreads from multiple convex transducers under a predetermined treatment program. We have discovered that by transmitting unfocused ultrasound energy to a wide range of the brain, it is possible to suppress the deterioration of the patient's cognitive function and treat dementia.
本発明はかかる新たな知見に基づくものであり、以下の発明を包含する。
［１］ 認知症の患者を治療するための方法であって、
複数の凸型トランスデューサーと、凸型トランスデューサーに配置され、脳に非集束超音波エネルギーを伝達する超音波振動子と、凸型トランスデューサーに接続された超音波発生装置を用いて、凸型トランスデューサーに配置された超音波振動子から発生する非集束超音波エネルギーを患者の脳に伝達させる工程を含み、
前記工程が、前記複数の凸型トランスデューサーの間で前記非集束超音波エネルギーを順次照射し、
前記非集束超音波エネルギーの照射を以下の治療プログラムに従って行う方法：
治療プログラム
１回の照射時間：１～６０分
１日治療：１日当たり照射回数が１～４回
１セッション：１日治療を、５日から１０日間に１～７回行う
セッション数：１セッション治療を４週間～１６週間毎に継続的に繰り返し、６セッション以上行う。
［２］ 前記治療プログラムにおいて、１回の照射時間を１５～２５分程度とし、１日当たりの照射回数を２～３回とする、［１］の方法。
［３］ 前記治療プログラムにおいて、１セッションにつき１日治療を隔日で、３回／週にて行う、［１］の方法。
［４］ 前記治療プログラムにおいて、１セッション治療を８～１２週毎に行う、［１］の方法。
［５］ 前記非集束超音波エネルギーの照射を、送信周波数：０．１～０．８ＭＨｚにて行う、［１］の方法。
［６］ 前記非集束超音波エネルギーの照射を、素子直下の音圧：０．１～１．５Ｍｐａにて行う、［１］の方法。
［７］ 前記非集束超音波エネルギーの照射を、１パルス当たりのサイクル数：１６～６４ｃｙｃｌｅにて行う、［１］の方法。
［８］ 前記非集束超音波エネルギーの照射を、パルス繰り返し周期（Pulse Repetition time；ＰＲＴ）：０．６～１．８ミリ秒にて行う、［１］の方法。
［９］ 前記非集束超音波エネルギーの照射を、超音波強度（ＩＳＰＴＡ）：７２０ｍＷ／ｃｍ２以下にて行う、［１］の方法。
［１０］ 前記非集束超音波エネルギーの照射を、以下の条件にて行う、［１］の方法：
送信周波数：０．５ＭＨｚ
素子直下の音圧：１．３ＭＰａ
１パルス当たりのサイクル数：３２ｃｙｃｌｅ
ＰＲＴ：１．２８ミリ秒
ＩＳＰＴＡ：２５０ｍＷ／ｃｍ２。
［１１］ 前記認知症の患者が、軽度アルツハイマー型認知症、又は軽度認知障害の患者である、［１］の方法。 The present invention is based on this new knowledge and includes the following inventions.
[1] A method for treating a patient with dementia, comprising:
Using multiple convex transducers, an ultrasound transducer placed on the convex transducer to transmit unfocused ultrasound energy to the brain, and an ultrasound generator connected to the convex transducer, the convex transmitting unfocused ultrasound energy generated from an ultrasound transducer disposed in a transducer to the patient's brain;
The step sequentially irradiates the unfocused ultrasound energy between the plurality of convex transducers,
A method of irradiating the unfocused ultrasound energy according to the following treatment program:
Treatment program Duration of one irradiation: 1 to 60 minutes Daily treatment: 1 to 4 irradiations perday 1 session: 1 day treatment, 1 to 7 times over 5 to 10 days Number of sessions: 1 session treatment Repeat this continuously every 4 to 16 weeks for 6 or more sessions.
[2] The method of [1], wherein in the treatment program, each irradiation time is about 15 to 25 minutes, and the number of irradiations per day is 2 to 3 times.
[3] The method of [1], wherein in the treatment program, one day of treatment per session is performed every other day, three times a week.
[4] The method of [1], wherein in the treatment program, one session treatment is performed every 8 to 12 weeks.
[5] The method of [1], wherein the irradiation of the unfocused ultrasonic energy is performed at a transmission frequency of 0.1 to 0.8 MHz.
[6] The method of [1], wherein the irradiation of the unfocused ultrasonic energy is performed at a sound pressure directly below the element: 0.1 to 1.5 MPa.
[7] The method of [1], wherein the irradiation of the unfocused ultrasonic energy is performed at a number of cycles per pulse: 16 to 64 cycles.
[8] The method of [1], wherein the irradiation of the unfocused ultrasound energy is performed at a pulse repetition time (PRT) of 0.6 to 1.8 milliseconds.
[9] The method of [1], wherein the irradiation of the unfocused ultrasound energy is performed at an ultrasound intensity (ISPTA) of 720 mW/cm 2 or less.
[10] The method of [1], wherein the irradiation of the unfocused ultrasonic energy is performed under the following conditions:
Transmission frequency: 0.5MHz
Sound pressure directly below the element: 1.3MPa
Number of cycles per pulse: 32 cycles
PRT: 1.28 ms ISPTA: 250 mW/cm 2 .
[11] The method of [1], wherein the dementia patient is a patient with mild Alzheimer's dementia or mild cognitive impairment.
［１］ 認知症の患者を治療するための方法であって、
複数の凸型トランスデューサーと、凸型トランスデューサーに配置され、脳に非集束超音波エネルギーを伝達する超音波振動子と、凸型トランスデューサーに接続された超音波発生装置を用いて、凸型トランスデューサーに配置された超音波振動子から発生する非集束超音波エネルギーを患者の脳に伝達させる工程を含み、
前記工程が、前記複数の凸型トランスデューサーの間で前記非集束超音波エネルギーを順次照射し、
前記非集束超音波エネルギーの照射を以下の治療プログラムに従って行う方法：
治療プログラム
１回の照射時間：１～６０分
１日治療：１日当たり照射回数が１～４回
１セッション：１日治療を、５日から１０日間に１～７回行う
セッション数：１セッション治療を４週間～１６週間毎に継続的に繰り返し、６セッション以上行う。
［２］ 前記治療プログラムにおいて、１回の照射時間を１５～２５分程度とし、１日当たりの照射回数を２～３回とする、［１］の方法。
［３］ 前記治療プログラムにおいて、１セッションにつき１日治療を隔日で、３回／週にて行う、［１］の方法。
［４］ 前記治療プログラムにおいて、１セッション治療を８～１２週毎に行う、［１］の方法。
［５］ 前記非集束超音波エネルギーの照射を、送信周波数：０．１～０．８ＭＨｚにて行う、［１］の方法。
［６］ 前記非集束超音波エネルギーの照射を、素子直下の音圧：０．１～１．５Ｍｐａにて行う、［１］の方法。
［７］ 前記非集束超音波エネルギーの照射を、１パルス当たりのサイクル数：１６～６４ｃｙｃｌｅにて行う、［１］の方法。
［８］ 前記非集束超音波エネルギーの照射を、パルス繰り返し周期（Pulse Repetition time；ＰＲＴ）：０．６～１．８ミリ秒にて行う、［１］の方法。
［９］ 前記非集束超音波エネルギーの照射を、超音波強度（ＩＳＰＴＡ）：７２０ｍＷ／ｃｍ２以下にて行う、［１］の方法。
［１０］ 前記非集束超音波エネルギーの照射を、以下の条件にて行う、［１］の方法：
送信周波数：０．５ＭＨｚ
素子直下の音圧：１．３ＭＰａ
１パルス当たりのサイクル数：３２ｃｙｃｌｅ
ＰＲＴ：１．２８ミリ秒
ＩＳＰＴＡ：２５０ｍＷ／ｃｍ２。
［１１］ 前記認知症の患者が、軽度アルツハイマー型認知症、又は軽度認知障害の患者である、［１］の方法。 The present invention is based on this new knowledge and includes the following inventions.
[1] A method for treating a patient with dementia, comprising:
Using multiple convex transducers, an ultrasound transducer placed on the convex transducer to transmit unfocused ultrasound energy to the brain, and an ultrasound generator connected to the convex transducer, the convex transmitting unfocused ultrasound energy generated from an ultrasound transducer disposed in a transducer to the patient's brain;
The step sequentially irradiates the unfocused ultrasound energy between the plurality of convex transducers,
A method of irradiating the unfocused ultrasound energy according to the following treatment program:
Treatment program Duration of one irradiation: 1 to 60 minutes Daily treatment: 1 to 4 irradiations per
[2] The method of [1], wherein in the treatment program, each irradiation time is about 15 to 25 minutes, and the number of irradiations per day is 2 to 3 times.
[3] The method of [1], wherein in the treatment program, one day of treatment per session is performed every other day, three times a week.
[4] The method of [1], wherein in the treatment program, one session treatment is performed every 8 to 12 weeks.
[5] The method of [1], wherein the irradiation of the unfocused ultrasonic energy is performed at a transmission frequency of 0.1 to 0.8 MHz.
[6] The method of [1], wherein the irradiation of the unfocused ultrasonic energy is performed at a sound pressure directly below the element: 0.1 to 1.5 MPa.
[7] The method of [1], wherein the irradiation of the unfocused ultrasonic energy is performed at a number of cycles per pulse: 16 to 64 cycles.
[8] The method of [1], wherein the irradiation of the unfocused ultrasound energy is performed at a pulse repetition time (PRT) of 0.6 to 1.8 milliseconds.
[9] The method of [1], wherein the irradiation of the unfocused ultrasound energy is performed at an ultrasound intensity (ISPTA) of 720 mW/cm 2 or less.
[10] The method of [1], wherein the irradiation of the unfocused ultrasonic energy is performed under the following conditions:
Transmission frequency: 0.5MHz
Sound pressure directly below the element: 1.3MPa
Number of cycles per pulse: 32 cycles
PRT: 1.28 ms ISPTA: 250 mW/cm 2 .
[11] The method of [1], wherein the dementia patient is a patient with mild Alzheimer's dementia or mild cognitive impairment.
本発明によれば、所定の治療プログラムの下、非集束超音波エネルギーを照射することにより、海馬や脳梁を含む脳組織の広い範囲に超音波エネルギーを伝達することができ、ヒト認知症患者の認知機能の悪化を抑制することができ、認知症を治療し得る。従って、本発明によれば、従来の認知症治療等とは異なる新たな認知症の治療方法を提供することができる。
According to the present invention, by irradiating unfocused ultrasound energy under a predetermined treatment program, it is possible to transmit ultrasound energy to a wide range of brain tissue including the hippocampus and corpus callosum, and to treat patients with dementia. It can suppress the deterioration of cognitive function and treat dementia. Therefore, according to the present invention, it is possible to provide a new method for treating dementia that is different from conventional dementia treatments.
本発明において「認知症」とは、軽度アルツハイマー型認知症、又は軽度認知障害を含み、好ましくは軽度アルツハイマー型認知症、又はアルツハイマー型認知症に由来する軽度認知障害である。ただし、アルツハイマー型認知症は脳血管性認知症など他の認知症との混合病理であることが多いため、本発明の認知症は脳血管性認知症を含むものであっても構わない。
In the present invention, "dementia" includes mild Alzheimer's type dementia or mild cognitive impairment, and is preferably mild Alzheimer's type dementia or mild cognitive impairment derived from Alzheimer's type dementia. However, since Alzheimer's dementia is often a mixed pathology with other dementias such as cerebrovascular dementia, the dementia of the present invention may include cerebrovascular dementia.
本発明において治療対象となる認知症患者は、認知症を罹患及び／又は認知症を罹患する虞のある哺乳動物が挙げられ、好ましくはヒトである。
Dementia patients to be treated in the present invention include mammals suffering from and/or at risk of suffering from dementia, preferably humans.
本発明において治療対象となる認知症患者は、米国精神医学会による精神疾患の診断・統計マニュアル第5版（DSM-5）及び／又は米国国立老化研究所とAlzheimer協会（NIA-AA）の診断基準に基づいて選定することができる。
好ましくは、本発明における治療対象となる認知症患者は、以下の一又は複数の基準に適合する患者である：
・米国精神医学会による精神疾患の診断・統計マニュアル第5版（DSM-5）における軽度アルツハイマー型認知症又は軽度認知障害の診断基準に適合する患者；
・米国国立老化研究所とAlzheimer協会（NIA-AA）の診断基準の「probable Alzheimer’s disease」または「MCI due to Alzheimer’s disease」に適合する患者；
・CDR global scoreで０．５～１．０点の患者；
・MMSE-Jスコアが２０点以上の患者。
ここで「複数」とは、二つ、三つ、又は四つを意味する。 Dementia patients to be treated in the present invention are diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) by the American Psychiatric Association and/or the National Institute on Aging and Alzheimer's Association (NIA-AA). Can be selected based on criteria.
Preferably, the dementia patient to be treated in the present invention is a patient who meets one or more of the following criteria:
・Patients who meet the diagnostic criteria for mild Alzheimer's dementia or mild cognitive impairment in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) by the American Psychiatric Association;
・Patients who meet the U.S. National Institute on Aging and Alzheimer's Association (NIA-AA) diagnostic criteria of "probable Alzheimer's disease" or "MCI due to Alzheimer's disease";
・Patients with a CDR global score of 0.5 to 1.0;
・Patients with MMSE-J score of 20 points or higher.
Here, "plurality" means two, three, or four.
好ましくは、本発明における治療対象となる認知症患者は、以下の一又は複数の基準に適合する患者である：
・米国精神医学会による精神疾患の診断・統計マニュアル第5版（DSM-5）における軽度アルツハイマー型認知症又は軽度認知障害の診断基準に適合する患者；
・米国国立老化研究所とAlzheimer協会（NIA-AA）の診断基準の「probable Alzheimer’s disease」または「MCI due to Alzheimer’s disease」に適合する患者；
・CDR global scoreで０．５～１．０点の患者；
・MMSE-Jスコアが２０点以上の患者。
ここで「複数」とは、二つ、三つ、又は四つを意味する。 Dementia patients to be treated in the present invention are diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) by the American Psychiatric Association and/or the National Institute on Aging and Alzheimer's Association (NIA-AA). Can be selected based on criteria.
Preferably, the dementia patient to be treated in the present invention is a patient who meets one or more of the following criteria:
・Patients who meet the diagnostic criteria for mild Alzheimer's dementia or mild cognitive impairment in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) by the American Psychiatric Association;
・Patients who meet the U.S. National Institute on Aging and Alzheimer's Association (NIA-AA) diagnostic criteria of "probable Alzheimer's disease" or "MCI due to Alzheimer's disease";
・Patients with a CDR global score of 0.5 to 1.0;
・Patients with MMSE-J score of 20 points or higher.
Here, "plurality" means two, three, or four.
本発明において、認知症の「治療」とは、認知症の完治もしくは治癒、あるいは、一部の又は全ての症状の一時的又は永続的な消失、軽減、緩和、又は進行（悪化／重症化）の防止もしくは低減（寛解）を意味する。例えば、本発明における認知症の「治療」には、認知症患者の認知機能の維持又は悪化の抑制、あるいは認知機能の改善が含まれる。認知症の治療の効果は、従来、認知症検査に用いられている手法を用いて評価することができ、このような手法としては、例えば、ＡＤＡＳ－ｃｏｇ(Alzheimer’s Disease Assessment Scale-cognitive subscale)、ＡＤＡＳ－Ｊｃｏｇ、CDR sum of boxes等が挙げられるが、これらに限定はされない。これらの手法は、認知機能又は認知症の重症度をスコア化することができ、治療経過における当該スコアの変化に基づいて、認知機能の維持又は悪化の抑制、あるいは認知機能の改善を評価することができ、認知症治療の効果を確認することができる。
In the present invention, "treatment" of dementia refers to complete cure or cure of dementia, or temporary or permanent disappearance, reduction, alleviation, or progression (worsening/increasing severity) of some or all symptoms. It means the prevention or reduction (remission) of For example, "treatment" of dementia in the present invention includes maintaining or suppressing deterioration of cognitive function of a patient with dementia, or improving cognitive function. The effectiveness of dementia treatment can be evaluated using methods conventionally used for dementia testing, such as ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale), Examples include, but are not limited to, ADAS-Jcog and CDR sum of boxes. These methods can score the severity of cognitive function or dementia, and based on changes in the score over the course of treatment, maintenance of cognitive function, suppression of deterioration, or improvement of cognitive function can be evaluated. It is possible to confirm the effectiveness of dementia treatment.
本発明は、認知症の患者を治療するための方法に関し、当該方法は、複数の凸型トランスデューサーと、凸型トランスデューサーに配置され、脳に非集束超音波エネルギーを伝達する超音波振動子と、凸型トランスデューサーに接続された超音波発生装置を用いて、凸型トランスデューサーに配置された超音波振動子から発生する非集束超音波エネルギーを患者の脳に伝達させる工程を含む。
本発明方法において、前記工程は、前記複数の凸型トランスデューサーの間で前記非集束超音波エネルギーを順次照射することを特徴とするものである。
また、本発明方法において、前記非集束超音波エネルギーの照射は、以下の治療プログラムに従って行うことを特徴とするものである：
治療プログラム
１回の照射時間：１～６０分
１日治療：１日当たり照射回数が１～４回
１セッション：１日治療を、５日から１０日間に１～７回行う
セッション数：１セッション治療を４週間～１６週間毎に継続的に繰り返し、６セッション以上行う。 The present invention relates to a method for treating a patient with dementia, the method comprising a plurality of convex transducers and an ultrasound transducer disposed on the convex transducer for transmitting unfocused ultrasound energy to the brain. and transmitting unfocused ultrasound energy generated from an ultrasound transducer disposed on the convex transducer to the patient's brain using an ultrasound generator connected to the convex transducer.
In the method of the present invention, the step is characterized in that the unfocused ultrasound energy is sequentially irradiated between the plurality of convex transducers.
Further, in the method of the present invention, the irradiation of the unfocused ultrasound energy is performed according to the following treatment program:
Treatment program Duration of one irradiation: 1 to 60 minutes Daily treatment: 1 to 4 irradiations perday 1 session: 1 day treatment, 1 to 7 times over 5 to 10 days Number of sessions: 1 session treatment Repeat this continuously every 4 to 16 weeks for 6 or more sessions.
本発明方法において、前記工程は、前記複数の凸型トランスデューサーの間で前記非集束超音波エネルギーを順次照射することを特徴とするものである。
また、本発明方法において、前記非集束超音波エネルギーの照射は、以下の治療プログラムに従って行うことを特徴とするものである：
治療プログラム
１回の照射時間：１～６０分
１日治療：１日当たり照射回数が１～４回
１セッション：１日治療を、５日から１０日間に１～７回行う
セッション数：１セッション治療を４週間～１６週間毎に継続的に繰り返し、６セッション以上行う。 The present invention relates to a method for treating a patient with dementia, the method comprising a plurality of convex transducers and an ultrasound transducer disposed on the convex transducer for transmitting unfocused ultrasound energy to the brain. and transmitting unfocused ultrasound energy generated from an ultrasound transducer disposed on the convex transducer to the patient's brain using an ultrasound generator connected to the convex transducer.
In the method of the present invention, the step is characterized in that the unfocused ultrasound energy is sequentially irradiated between the plurality of convex transducers.
Further, in the method of the present invention, the irradiation of the unfocused ultrasound energy is performed according to the following treatment program:
Treatment program Duration of one irradiation: 1 to 60 minutes Daily treatment: 1 to 4 irradiations per
図３に、本発明方法において利用される凸型トランスデューサーの一実施形態の概略図を示す。凸型トランスデューサー１は、コネクタ部３を備えたケーブル部２を介して、超音波発生装置（図示せず）に接続される。凸型トランスデューサーには脳に非集束超音波エネルギーを伝達する超音波振動子４が配置されている。
FIG. 3 shows a schematic diagram of an embodiment of a convex transducer used in the method of the present invention. The convex transducer 1 is connected to an ultrasound generator (not shown) via a cable section 2 having a connector section 3 . An ultrasound transducer 4 is arranged in the convex transducer to transmit unfocused ultrasound energy to the brain.
本発明において、超音波振動子の素材としては、上記非集束超音波エネルギーを発生できるものであれば特に限定されないが、例えば、樹脂（ノリル樹脂、ポリアセタール、アイオノマー樹脂、ウレタン樹脂等）、金属（銅合金等）等が挙げられる。また、凸型トランスデューサーのうち、超音波を発生させる部分の大きさは、特に限定されないが、例えば、超音波を発生させる部分の形状が略円形の場合、その直径は、１．０～６．０ｃｍが好ましく、２．０～５．０ｃｍがより好ましく、３．０～４．８ｃｍとすることがさらに好ましい。また、当該トランスデューサーにおける超音波を発生させる部分の形状は特に限定されず、略円形、略楕円形、多角形（三角形、四角形（正方形、長方形、平行四辺形、台形等）、五角形、六角形、七角形、八角形等）等、適宜設計することができる。またその寸法についても、超音波が脳のより広い分野に伝達するよう、例えば、略円形について上述したものに相当するような寸法で、適宜設定できる。
In the present invention, the material of the ultrasonic transducer is not particularly limited as long as it can generate the above-mentioned unfocused ultrasonic energy, but examples include resins (noryl resin, polyacetal, ionomer resin, urethane resin, etc.), metals ( copper alloys, etc.). Furthermore, the size of the portion of the convex transducer that generates ultrasonic waves is not particularly limited, but for example, if the portion that generates ultrasonic waves has a substantially circular shape, the diameter is 1.0 to 6 mm. 0 cm is preferable, 2.0 to 5.0 cm is more preferable, and even more preferably 3.0 to 4.8 cm. Further, the shape of the part of the transducer that generates ultrasonic waves is not particularly limited, and may be approximately circular, approximately elliptical, polygonal (triangle, quadrilateral (square, rectangle, parallelogram, trapezoid, etc.), pentagon, hexagon, etc.). , heptagon, octagon, etc.) can be designed as appropriate. Further, its dimensions can be appropriately set, for example, to correspond to the dimensions described above for the approximately circular shape so that the ultrasound waves are transmitted to a wider area of the brain.
本発明においては、典型的には、１つの凸型トランスデューサー１に対し、図３に示すように、単一の超音波振動子４が配置される。超音波振動子４には、ケーブル部２を介して、超音波発生装置から電気が送電されて電圧がかけられ、これにより、超音波振動子４は振動する。超音波振動子４の振動の周波数、時間、タイミング等は、超音波発生装置により制御される。また、超音波発生装置からの制御信号を切り替えることにより、同じ超音波振動子４を超音波受信素子として作用させることができる。このような受信素子を備える実施形態においては、凸型トランスデューサーから発信され、脳を透過した超音波の強度が予め想定した範囲にあるか否かをモニターできるため好ましい。尚、自身の送信超音波を受信し、これを用いることもできる。
In the present invention, typically, a single ultrasonic transducer 4 is arranged for one convex transducer 1, as shown in FIG. Electricity is transmitted from the ultrasonic generator to the ultrasonic vibrator 4 via the cable portion 2, and a voltage is applied to the ultrasonic vibrator 4, thereby causing the ultrasonic vibrator 4 to vibrate. The vibration frequency, time, timing, etc. of the ultrasonic transducer 4 are controlled by the ultrasonic generator. Further, by switching the control signals from the ultrasonic generator, the same ultrasonic transducer 4 can be made to function as an ultrasonic receiving element. An embodiment including such a receiving element is preferable because it is possible to monitor whether the intensity of the ultrasound transmitted from the convex transducer and transmitted through the brain is within a predetermined range. Note that it is also possible to receive and use its own transmitted ultrasonic waves.
本発明においては、超音波を非集束方向で進めるよう１つの超音波振動子の超音波照射面を凸曲面形状とするか、複数の超音波振動子を凸曲面形状に配置することにより、非集束超音波エネルギーを脳、好ましくは脳全体に対し効率的に伝達でき、その結果、ｅＮＯＳの発現が亢進し、ＡβやＡβの前駆体タンパク質（Amyloid precursor protein、ＡＰＰ）の生成を抑制したり、血管新生して神経再生したり、神経栄養因子の発現を亢進したり、タウ蛋白質のリン酸化を抑制することで認知症を治療することができる。
In the present invention, the ultrasonic irradiation surface of one ultrasonic transducer has a convex curved shape so that the ultrasonic waves advance in a non-focused direction, or by arranging a plurality of ultrasonic transducers in a convex curved shape, Focused ultrasound energy can be efficiently transmitted to the brain, preferably to the whole brain, and as a result, the expression of eNOS is enhanced, and the production of Aβ and Aβ precursor protein (Amyloid precursor protein, APP) is suppressed. Dementia can be treated by regenerating nerves through angiogenesis, increasing the expression of neurotrophic factors, and suppressing phosphorylation of tau protein.
本発明において、「非集束超音波エネルギー」とは、１点もしくは一本の線に集束せずに、拡散する超音波エネルギーを意味する。本発明においては、非集束超音波エネルギーが放射方向に向かって次第に拡径する逆テーパ状に拡散することが好ましい。前記拡径する逆テーパ状の非集束超音波エネルギーの傾斜面の広がる角度が５０°～１００°であることが好ましく、６０°～９０°であることがより好ましい。典型的には、超音波エネルギーは、図４（１）に示すように略円錐状（底面部分は曲面となり得る）に拡散される。放射方向に向かって次第に拡径する逆テーパ状に拡散する実施形態における凸型トランスデューサー１の側面図を図４（２）に示す。本発明においては、拡径する逆テーパ状の非集束超音波エネルギーの傾斜面の広がる角度とは、図４（２）におけるθを意味する。
In the present invention, "unfocused ultrasonic energy" refers to ultrasonic energy that is diffused without being focused on one point or line. In the present invention, it is preferable that the unfocused ultrasound energy is diffused in a reverse taper shape that gradually expands in diameter in the radial direction. It is preferable that the angle at which the inclined surface of the inverted tapered unfocused ultrasonic energy expanding in diameter spreads is 50° to 100°, more preferably 60° to 90°. Typically, the ultrasonic energy is diffused in a substantially conical shape (the bottom portion may be a curved surface) as shown in FIG. 4(1). FIG. 4(2) shows a side view of the convex transducer 1 in an embodiment in which the convex transducer 1 is diffused in an inverted tapered shape whose diameter gradually expands in the radial direction. In the present invention, the angle at which the inclined surface of the inverted tapered unfocused ultrasonic energy expands means θ in FIG. 4(2).
本発明方法の典型的な実施形態においては、図５に示されるように、複数（図５では２つの）凸型トランスデューサー１が患者の頭部に当てられた状態で行われる。凸型トランスデューサー１が当てられる場所は特に限定されないが、頭蓋骨が比較的薄く超音波を脳に伝達しやすくするため、側頭部（こめかみ）に当てることが好ましい。凸型トランスデューサー１は、ヘッドセット５に取り付けられ、患者はこのヘッドセットを装着することにより、２つの凸型トランスデューサーを側頭部に配置することができる。また、治療を受ける間の患者の姿勢は、座位であっても、臥位であってもよい。側頭部に配置された凸型トランスデューサーより、上記のように、非集束超音波エネルギーを逆テーパ状に拡散させることにより、脳の大部分、例えば、少なくとも海馬及び脳梁を含む部分、典型的には脳の全体に対し超音波エネルギーを伝達することできるため、好ましい（図６）。超音波が効率よく脳に伝達されるように、また、凸型トランスデューサーとの接触部における患者組織の発熱を抑えるために、凸型トランスデューサー１の超音波発生部分及び／又は凸型トランスデューサーを当てる頭部の部分に適宜ジェル（エコージェル、エコーゼリー等とも称される）を塗っておいてもよい。
In a typical embodiment of the method of the present invention, as shown in FIG. 5, the method is performed with a plurality of (two in FIG. 5) convex transducers 1 placed against the patient's head. The location where the convex transducer 1 is applied is not particularly limited, but it is preferably applied to the temporal region (temple) because the skull is relatively thin and it is easy to transmit ultrasound to the brain. The convex transducer 1 is attached to a headset 5, and by wearing this headset, the patient can place two convex transducers on the side of his head. Furthermore, the patient's posture while undergoing treatment may be a sitting position or a supine position. As described above, the convex transducer placed in the temporal region spreads unfocused ultrasound energy in an inversely tapered manner, thereby transmitting a large portion of the brain, for example, at least a portion including the hippocampus and corpus callosum, typically Specifically, it is preferable because it can transmit ultrasound energy to the entire brain (Fig. 6). In order to efficiently transmit ultrasound waves to the brain and to suppress heat generation of patient tissue at the contact area with the convex transducer, the ultrasound generating portion of the convex transducer 1 and/or the convex transducer You may also apply an appropriate gel (also called echo gel, echo jelly, etc.) to the part of the head that is to be applied.
本発明においては、凸型トランスデューサーを複数用い、頭部の異なる箇所から非集束超音波エネルギーを照射することにより、脳のより広い範囲に超音波エネルギーを伝達できる。本発明においては、安全性の観点、より具体的には、複数の箇所から照射される超音波エネルギーが脳内に重複して伝達され、その結果、過剰な超音波エネルギーが脳内に伝達されることを抑制する観点から、複数の凸型トランスデューサーの間で非集束超音波エネルギーを順次照射する。本発明において、「複数の凸型トランスデューサーの間で非集束超音波エネルギーを順次照射する」とは、まず複数の凸型トランスデューサーのうち、ある凸型トランスデューサーで超音波を発生させ、その間、その他の凸型トランスデューサーで超音波を発生させず、次に別の凸型トランスデューサーで超音波を発生させ、その間、その他の凸型トランスデューサーで超音波を発生させず・・・というように、複数の凸型トランスデューサーのうち、同じ時間帯で超音波を発生させている凸型トランスデューサーが１つのみであること、言い換えると２つ以上から同時に超音波を発生させないことを意味する。
In the present invention, by using a plurality of convex transducers and emitting unfocused ultrasound energy from different parts of the head, ultrasound energy can be transmitted to a wider range of the brain. In the present invention, from the viewpoint of safety, more specifically, ultrasound energy irradiated from multiple locations is transmitted redundantly into the brain, and as a result, excessive ultrasound energy is transmitted into the brain. In order to suppress this phenomenon, unfocused ultrasound energy is sequentially irradiated between multiple convex transducers. In the present invention, "sequentially irradiating unfocused ultrasound energy between a plurality of convex transducers" means to first generate ultrasonic waves with a certain convex transducer among the plurality of convex transducers, and then , the other convex transducer does not generate ultrasonic waves, then another convex transducer generates ultrasonic waves, while the other convex transducers do not generate ultrasonic waves, and so on. Among multiple convex transducers, only one convex transducer is generating ultrasonic waves at the same time; in other words, two or more convex transducers do not generate ultrasonic waves at the same time. .
本発明において、凸型トランスデューサーから発生した超音波は、頭蓋骨を透過し、脳に伝達して、当該凸型トランスデューサーを配置したのとは反対側の頭蓋骨で反射して当該凸型トランスデューサーの方向に再度伝達する。そして、当該反射した超音波は、当該凸型トランスデューサーを配置した側の頭蓋骨で再度反射して伝達をする。この間、超音波は、脳内を伝播する際及び頭蓋骨で反射する際に減衰する。このように、凸型トランスデューサーから発生した超音波は、頭蓋骨で反射するたびに減衰しながら、脳内を複数回往復する。
In the present invention, the ultrasound generated from the convex transducer passes through the skull, is transmitted to the brain, and is reflected by the skull on the opposite side to where the convex transducer is placed. Transmit again in the direction of. Then, the reflected ultrasonic waves are reflected again by the skull on the side where the convex transducer is placed and transmitted. During this time, the ultrasound waves are attenuated as they propagate through the brain and reflect off the skull. In this way, the ultrasound generated by the convex transducer travels back and forth within the brain multiple times, attenuating each time it reflects off the skull.
従って、本発明において複数の凸型トランスデューサーの間で非集束超音波エネルギーを順次照射をする場合、ある凸型トランスデューサーから発生した非集束超音波エネルギーの照射波又は反射波が減衰して、次の凸型トランスデューサーから発生した非集束超音波エネルギーと重複しても過剰な超音波刺激とならないように、複数の凸型トランスデューサーからの超音波の発生間隔を空けることが好ましい。上記の観点から、本発明においては、複数の凸型トランスデューサーによる非集束超音波エネルギー照射の間隔は、パルス繰り返し周期（Pulse Repetition Time；ＰＲＴ）で表すことができ、ＰＲＴは０．６～１．８ミリ秒の範囲で適宜設定することが好ましく、より好ましくは１．２８ミリ秒である。本発明においてＰＲＴをこの範囲に設定することにより、次の非集束超音波エネルギー照射の前に、照射された超音波は上述のとおり頭蓋骨内を往復して減衰し（好ましくは１／１００程度にまで減衰し）、脳内における超音波エネルギーの重複による過剰な超音波刺激を回避又は低減することができる。
Therefore, in the present invention, when unfocused ultrasonic energy is sequentially irradiated between a plurality of convex transducers, the emitted wave or reflected wave of unfocused ultrasonic energy generated from a certain convex transducer is attenuated. It is preferable to leave intervals between the generation of ultrasound waves from the plurality of convex transducers so that excessive ultrasound stimulation does not occur even if the unfocused ultrasound energy is overlapped with the unfocused ultrasound energy generated from the next convex transducer. From the above point of view, in the present invention, the interval between unfocused ultrasound energy irradiation by a plurality of convex transducers can be expressed as a pulse repetition time (PRT), and PRT is 0.6 to 1 It is preferable to set the time appropriately within a range of .8 milliseconds, and more preferably 1.28 milliseconds. In the present invention, by setting PRT within this range, the irradiated ultrasound waves are attenuated by reciprocating within the skull as described above (preferably to about 1/100) before the next unfocused ultrasound energy irradiation. (attenuated up to 100%), and excessive ultrasound stimulation due to duplication of ultrasound energy in the brain can be avoided or reduced.
ここで、非集束超音波エネルギー照射の間隔とは、そうでないことを明記しない限り、ある凸型トランスデューサーから超音波照射を開始し、当該凸型トランスデューサーからの超音波照射を停止し、次の凸型トランスデューサーから超音波照射を開始し、当該次の凸型トランスデューサーからの超音波照射を停止し・・・という照射をする際、上記趣旨から、ある凸型トランスデューサーからの超音波照射の開始から、次の凸型トランスデューサーでの超音波照射の開始までの時間を意味する。
Unless otherwise specified, the interval between unfocused ultrasonic energy irradiations means starting ultrasonic irradiation from one convex transducer, stopping ultrasonic irradiation from that convex transducer, and then When performing irradiation such as starting ultrasonic irradiation from one convex transducer, stopping ultrasonic irradiation from the next convex transducer, etc., from the above purpose, if It means the time from the start of irradiation to the start of ultrasound irradiation with the next convex transducer.
本発明において、凸型トランスデューサーによる非集束超音波エネルギーの照射は、素子（超音波振動子）直下の照射超音波の振幅（音圧）が、０．１～１．５ＭＰａとなる範囲で適宜設定することが可能であり、好ましくは０．３～１．３ＭＰａ、より好ましくは１．３ＭＰａである。素子直下の音圧をこの範囲に設定することにより、組織に作用する音圧を０．０５～０．５ＭＰａとする緩やかなＬＩＰＵＳ刺激によりｅＮＯＳ等の発現亢進を促し、治療の有効性を得ることができる（図７：特許文献７）。凸型トランスデューサーの振動子の指向特性は、ハイドロフォン法により計測した参考計測値（音圧）として、例えば、図８のようになり、素子直下が最も高エネルギーとなる。
In the present invention, the irradiation of unfocused ultrasonic energy by the convex transducer is performed appropriately within the range where the amplitude (sound pressure) of the irradiated ultrasonic wave directly below the element (ultrasonic transducer) is 0.1 to 1.5 MPa. It is possible to set it to be preferably 0.3 to 1.3 MPa, more preferably 1.3 MPa. By setting the sound pressure directly below the element within this range, gentle LIPUS stimulation with a sound pressure acting on the tissue of 0.05 to 0.5 MPa can promote the expression of eNOS, etc., and obtain therapeutic effectiveness. (Figure 7: Patent Document 7). The directivity characteristics of the vibrator of the convex transducer are as shown in FIG. 8, for example, as a reference measurement value (sound pressure) measured by the hydrophone method, with the highest energy directly below the element.
また、本発明において、超音波の送信周波数（Frequency）は、０．１～０．８ＭＨｚの範囲で適宜設定することが可能であり、好ましくは０．５ＭＨｚである。
Furthermore, in the present invention, the ultrasonic transmission frequency can be appropriately set in the range of 0.1 to 0.8 MHz, and is preferably 0.5 MHz.
また、本発明において、照射超音波は非連続波であり、そのサイクル数は１パルス当たり１６～３４ｃｙｃｌｅの範囲で適宜設定することが可能であり、好ましくは３２ｃｙｃｌｅである。ここで、超音波のサイクル数とは、超音波照射の開始から超音波照射停止までの幅（本明細書においてパルス幅とも示す）内でのサイクル数を示す。超音波のサイクル数を３２ｃｙｃｌｅ程度とすることによって、脳内におけるｅＮＯＳやＶＥＧＦ等の発現を亢進できる（非特許文献５）。
Furthermore, in the present invention, the irradiated ultrasonic wave is a discontinuous wave, and the number of cycles thereof can be appropriately set in the range of 16 to 34 cycles per pulse, and is preferably 32 cycles. Here, the number of cycles of ultrasound refers to the number of cycles within the width (also referred to as pulse width in this specification) from the start of ultrasound irradiation to the end of ultrasound irradiation. By setting the number of ultrasound cycles to about 32 cycles, expression of eNOS, VEGF, etc. in the brain can be enhanced (Non-Patent Document 5).
超音波の強度（Intensity）は、ＩＳＰＰＡ、ＩＳＰＴＡ等により調整することができる。ここで、ＩＳＰＰＡとは、パルス幅内の平均強度を示す。ＩＳＰＴＡとは、繰返し周期内の平均強度を示す。
The intensity of the ultrasonic waves can be adjusted by ISPPA, ISPTA, etc. Here, ISPPA indicates the average intensity within the pulse width. ISPTA indicates the average intensity within a repetition period.
照射超音波のＩＳＰＴＡは特に限定されないが、緩やかな超音波刺激により血管新生、ニューロン増加等を促す観点から、例えば、７２０ｍＷ／ｃｍ２以下、好ましくは１００～５００ｍＷ／ｃｍ２の範囲で適宜設定でき、より好ましくは２５０ｍＷ／ｃｍ２である。複数の凸型トランスデューサーを用いる場合、ＩＳＰＴＡは、各凸型トランスデューサーの照射超音波のＩＳＰＴＡの和で表現される。
The ISPTA of the irradiated ultrasound is not particularly limited, but can be set as appropriate in the range of, for example, 720 mW/cm 2 or less, preferably 100 to 500 mW/cm 2 from the viewpoint of promoting angiogenesis, neuron increase, etc. through gentle ultrasound stimulation. , more preferably 250 mW/cm 2 . When a plurality of convex transducers are used, the ISPTA is expressed as the sum of the ISPTA of the irradiated ultrasound waves of each convex transducer.
また、本発明において、照射超音波のパルス繰り返し周波数（Pulse Repetition Frequency；ＰＲＦ）は、ＰＲＴの逆数のため、５５６～１６６７Ｈｚの範囲で適宜設定することが可能であり、好ましくは７８１Ｈｚである。
Furthermore, in the present invention, the pulse repetition frequency (PRF) of the irradiated ultrasound wave is the reciprocal of PRT, so it can be appropriately set in the range of 556 to 1667 Hz, and is preferably 781 Hz.
また、本発明において、照射超音波のＤｕｔｙ比（Duty Cycle）は周波数、サイクル数、ＰＲＴで一義的に決まるので特に規定しないが好ましくは１～３０％である。
Furthermore, in the present invention, the duty ratio (Duty Cycle) of the irradiated ultrasound is uniquely determined by the frequency, number of cycles, and PRT, so it is not particularly specified, but is preferably 1 to 30%.
ここで、Ｄｕｔｙ比とは、一定時間超音波を照射し、一定時間超音波照射を休止する、という１サイクルの時間の中で、超音波の照射時間の割合を示す。いいかえると、１サイクル中の［超音波の照射時間＋照射休止時間］に対する超音波の照射時間の割合を示す。複数の凸型トランスデューサーを用いる場合、Ｄｕｔｙ比は、各凸型トランスデューサーの照射超音波のＤｕｔｙ比の和で表現される。
Here, the duty ratio indicates the ratio of the ultrasonic irradiation time in one cycle of irradiating ultrasonic waves for a certain period of time and stopping the ultrasonic irradiation for a certain period of time. In other words, it shows the ratio of the ultrasonic irradiation time to [ultrasonic irradiation time + irradiation pause time] during one cycle. When using a plurality of convex transducers, the duty ratio is expressed as the sum of the duty ratios of the irradiated ultrasonic waves of each convex transducer.
なお、凸型トランスデューサーから発生した超音波は、頭蓋骨を透過する際に、大幅に減衰する。また、減衰の程度は、超音波が透過する頭蓋骨の厚さにより変化することが知られている（特許文献７）。従って、認知症の診断時に撮影された頭部CT画像等に基づき頭蓋骨の厚さの数値をもとに適切な出力の推定値を算出し、治療用超音波として発信することも好ましい。
Note that the ultrasound generated from the convex transducer is significantly attenuated when passing through the skull. Furthermore, it is known that the degree of attenuation changes depending on the thickness of the skull through which ultrasound waves pass (Patent Document 7). Therefore, it is also preferable to calculate an appropriate estimated output value based on the numerical value of the skull thickness based on a head CT image taken at the time of diagnosis of dementia, and transmit it as therapeutic ultrasound.
本発明における治療プロトコルおいて、非集束超音波エネルギーの照射による治療時間は、超音波振動子から発生する非集束超音波エネルギーを患者の脳に伝達させることができればよく特に限定されるものではないが、例えば、患者の症状、超音波の強度等の要因に応じて適宜決定することができ、治療１回あたりの照射時間は、好ましくは１～６０分、より好ましくは１５～２５分の範囲で適宜決定することができ、特に好ましくは２０分である。また、１日あたりの非集束超音波エネルギーの照射回数（すなわち、１日治療における照射回数）は、複数回行うことも可能であり、特に限定されないが、１日治療として、例えば、１回～４回、好ましくは２回～３回の範囲で適宜設定することができ、より好ましくは３回である。各回は適宜間隔を設けて行うことができ、特に限定はされないが、少なくとも５分以上の間隔を空けて実施するのが好ましい。
In the treatment protocol of the present invention, the treatment time for irradiation with unfocused ultrasound energy is not particularly limited as long as the unfocused ultrasound energy generated from the ultrasound transducer can be transmitted to the patient's brain. However, it can be determined as appropriate depending on factors such as the patient's symptoms and the intensity of ultrasound, and the irradiation time per treatment is preferably in the range of 1 to 60 minutes, more preferably 15 to 25 minutes. The time can be determined as appropriate, particularly preferably 20 minutes. Furthermore, the number of irradiations with unfocused ultrasound energy per day (i.e., the number of irradiations in one day treatment) can be performed multiple times, and is not particularly limited; It can be set appropriately in the range of 4 times, preferably 2 to 3 times, and more preferably 3 times. Each session can be carried out at appropriate intervals, and although not particularly limited, it is preferable to carry out the sessions at intervals of at least 5 minutes or more.
上記「１日治療」を実施する頻度は特に限定されず、例えば、患者の症状、超音波の強度等の要因に応じて適宜決定することができ、５日から１０日間、好ましくは５日から８日日間、より好ましくは５日間に、好ましくは１回～７回の範囲で適宜決定することができ、より好ましくは２回～３回の範囲で適宜設定することができ、それらは、隔日に設定されることがさらに好ましい。
The frequency with which the above-mentioned "one-day treatment" is performed is not particularly limited, and can be determined as appropriate depending on factors such as the patient's symptoms and the intensity of ultrasound, and is preferably for 5 to 10 days, preferably 5 to 10 days. The number of times can be determined as appropriate within the range of 8 days, more preferably 5 days, preferably 1 to 7 times, and more preferably 2 to 3 times, and these times may be set every other day. More preferably, it is set to .
本発明においては、上記１日治療を上記頻度で行うこと（例えば、上記１日治療を５日から１０日間に１～７回行うこと）を「１セッション」の治療とすることができる。本発明において、セッション数は特に限定されず、例えば、患者の症状、超音波の強度等の要因に応じて適宜決定することができるが、好ましくは６セッション以上、より好ましくは６～９セッションであり、有害事象の発生等がない限り、継続的に行うことができる。各セッションの間隔は特に限定されず、例えば、患者の症状、超音波の強度等の要因に応じて適宜決定することができ、好ましくは、４週間～１６週間に１セッションの間隔で適宜決定することができ、より好ましくは８～１２週間に１セッションの間隔である。本発明者らは、ＬＩＰＵＳ照射の効果発現に要する時間として、ｍＲＮＡ（ＲＴ－ＰＣＲ）で３～２４時間、タンパク質発現（Ｗｅｓｔｅｒｎ）で１週間、組織で４週間、を要することを確認しているため（非特許文献４，５、９）、ＬＩＰＵＳ照射後の組織変化後に次のセッションを行うことを想定すると、各セッション間隔は４週間以上おくことが望ましく、８～１２週間のセッション間隔で６セッション以上行うことがさらに好ましい。
In the present invention, performing the one-day treatment at the frequency described above (for example, performing the one-day treatment 1 to 7 times from 5th to 10th day) can be considered a "1 session" treatment. In the present invention, the number of sessions is not particularly limited and can be determined as appropriate depending on factors such as the patient's symptoms and the intensity of ultrasound, but is preferably 6 or more sessions, more preferably 6 to 9 sessions. Yes, and it can be continued as long as no adverse events occur. The interval between each session is not particularly limited, and can be determined as appropriate depending on factors such as the patient's symptoms and the intensity of ultrasound, and is preferably determined at an interval of one session every 4 to 16 weeks. more preferably one session every 8 to 12 weeks. The present inventors have confirmed that the time required for the effect of LIPUS irradiation to occur is 3 to 24 hours for mRNA (RT-PCR), 1 week for protein expression (Western), and 4 weeks for tissue. ( Non-patent Documents 4, 5, 9), assuming that the next session will be performed after the tissue change after LIPUS irradiation, it is desirable to have at least 4 weeks between each session, and 6 to 6 sessions with an 8 to 12 week interval. It is more preferable to conduct more than one session.
以上、特定の実施形態を示す図面に基づき、本発明を説明したが、本発明は、これらの実施形態に特定されないことは明らかである。例えば、凸型トランスデューサーと超音波発生装置との接続は、図３や５に記載のように有線でもよいし、あるいは無線でもよい。凸型トランスデューサーの数についても、２つの凸型トランスデューサーを用いる実施形態により説明してきたが、３つ以上の凸型トランスデューサーを用いてもよい。例えば、２つの凸型トランスデューサーを両側頭部（こめかみ）に当て、別途１つの超音波プローブを後頭部と項部との境界部（大後頭孔）に当てて超音波照射することもできる。
Although the present invention has been described above based on the drawings showing specific embodiments, it is clear that the present invention is not limited to these embodiments. For example, the connection between the convex transducer and the ultrasonic generator may be wired as shown in FIGS. 3 and 5, or may be wireless. Regarding the number of convex transducers, although the embodiment using two convex transducers has been described, three or more convex transducers may be used. For example, two convex transducers can be placed on both sides of the head (temples), and a separate ultrasonic probe can be placed on the boundary between the occipital region and the nuchal region (foramen magnum) to irradiate ultrasound.
以下、本発明を特定の実施例を挙げて例示するが、本発明はこれらの実施例に限定されない。
Hereinafter, the present invention will be illustrated with specific examples, but the present invention is not limited to these examples.
実施例１：ＬＩＰＵＳ治療時の組織温度上昇のシミュレーション
超音波照射による脳組織全体での温度上昇は、脳組織全体では灌流があるため、数分で定常状態に達すると考えられる。図９において、素子直下音圧1.3MPaの場合、78ｍｍ深さでの平均音圧はハイドロフォン測定より3.622 mW/cm2と試算された。これより総パワーを計算すると
3.9 cm×3.9 cm×3.14×3.622 mW/cm2 =174.7 mW ≒ 175 mW
となる。 Example 1: Simulation of tissue temperature increase during LIPUS treatment The temperature increase in the entire brain tissue due to ultrasound irradiation is thought to reach a steady state in a few minutes because there is perfusion in the entire brain tissue. In Figure 9, when the sound pressure directly below the element is 1.3 MPa, the average sound pressure at a depth of 78 mm is estimated to be 3.622 mW/cm 2 from hydrophone measurements. Calculating the total power from this: 3.9 cm×3.9 cm×3.14×3.622 mW/cm 2 =174.7 mW ≒ 175 mW
becomes.
超音波照射による脳組織全体での温度上昇は、脳組織全体では灌流があるため、数分で定常状態に達すると考えられる。図９において、素子直下音圧1.3MPaの場合、78ｍｍ深さでの平均音圧はハイドロフォン測定より3.622 mW/cm2と試算された。これより総パワーを計算すると
3.9 cm×3.9 cm×3.14×3.622 mW/cm2 =174.7 mW ≒ 175 mW
となる。 Example 1: Simulation of tissue temperature increase during LIPUS treatment The temperature increase in the entire brain tissue due to ultrasound irradiation is thought to reach a steady state in a few minutes because there is perfusion in the entire brain tissue. In Figure 9, when the sound pressure directly below the element is 1.3 MPa, the average sound pressure at a depth of 78 mm is estimated to be 3.622 mW/cm 2 from hydrophone measurements. Calculating the total power from this: 3.9 cm×3.9 cm×3.14×3.622 mW/cm 2 =174.7 mW ≒ 175 mW
becomes.
ワーストケースとして、超音波照射された部分の体積のみに対してエネルギーが熱として蓄えられると仮定すると超音波照射部位（図９の斜線部分）の体積はおおよそ
3 cm×3 cm × (24-12) cm×1/ 3= 113.04 cm3
であり、約１分間で各臓器は灌流されることから
脳組織の1 mL ≒ 1 cm3とすると、照射部位の潅流血流量は
113.04 mL/min ＝1.88 mL/sec程度となり、組織温度上昇は、
175 mW ＝0.175 J/sec＝0.04 cal/sec
0.04 cal / 1.88 g = 0.02 ℃
となる。 In the worst case, assuming that energy is stored as heat only in the volume of the ultrasound irradiated area, the volume of the ultrasound irradiation area (the shaded area in Figure 9) is approximately 3 cm × 3 cm × (24-12 ) cm×1/ 3= 113.04 cm 3
Since each organ is perfused in approximately 1 minute, assuming that 1 mL of brain tissue = 1 cm3 , the perfusion blood flow rate at the irradiation site is approximately 113.04 mL/min = 1.88 mL/sec, and the tissue temperature rise is approximately ,
175 mW = 0.175 J/sec = 0.04 cal/sec
0.04 cal / 1.88 g = 0.02℃
becomes.
3 cm×3 cm × (24-12) cm×1/ 3= 113.04 cm3
であり、約１分間で各臓器は灌流されることから
脳組織の1 mL ≒ 1 cm3とすると、照射部位の潅流血流量は
113.04 mL/min ＝1.88 mL/sec程度となり、組織温度上昇は、
175 mW ＝0.175 J/sec＝0.04 cal/sec
0.04 cal / 1.88 g = 0.02 ℃
となる。 In the worst case, assuming that energy is stored as heat only in the volume of the ultrasound irradiated area, the volume of the ultrasound irradiation area (the shaded area in Figure 9) is approximately 3 cm × 3 cm × (24-12 ) cm×1/ 3= 113.04 cm 3
Since each organ is perfused in approximately 1 minute, assuming that 1 mL of brain tissue = 1 cm3 , the perfusion blood flow rate at the irradiation site is approximately 113.04 mL/min = 1.88 mL/sec, and the tissue temperature rise is approximately ,
175 mW = 0.175 J/sec = 0.04 cal/sec
0.04 cal / 1.88 g = 0.02℃
becomes.
一方、天秤法による測定結果から、総パワーは、268 mW ≒ 270 mWであったことから、組織温度上昇は、
270 mW ＝0.27 J/sec＝0.06 cal/sec
0.06 cal / 1.88 g = 0.03 ℃
となり、定常状態では0.02～0.03 ℃の組織温度上昇になると考えられる。 On the other hand, the measurement results using the balance method showed that the total power was 268 mW ≒ 270 mW, so the tissue temperature increase was
270 mW = 0.27 J/sec = 0.06 cal/sec
0.06 cal / 1.88 g = 0.03℃
Therefore, in steady state, the tissue temperature is thought to increase by 0.02 to 0.03 °C.
270 mW ＝0.27 J/sec＝0.06 cal/sec
0.06 cal / 1.88 g = 0.03 ℃
となり、定常状態では0.02～0.03 ℃の組織温度上昇になると考えられる。 On the other hand, the measurement results using the balance method showed that the total power was 268 mW ≒ 270 mW, so the tissue temperature increase was
270 mW = 0.27 J/sec = 0.06 cal/sec
0.06 cal / 1.88 g = 0.03℃
Therefore, in steady state, the tissue temperature is thought to increase by 0.02 to 0.03 °C.
すなわち、ハイドロフォン法・天秤法という二つの実験系いずれにおいてもワーストケースでの温度上昇でさえ体温の日内変動（約１℃）よりも少ない温度上昇であり、本発明の照射条件は安全と考えられる。
In other words, in both the hydrophone method and the balance method, the temperature rise in the worst case is smaller than the diurnal fluctuation of body temperature (approximately 1°C), and the irradiation conditions of the present invention are considered safe. It will be done.
さらに実際には脳組織全体での灌流があり、頭蓋内容量は男性で平均1260 mL（1050-1500 mL）、女性で平均1130 mL（950-1400 mL）であることから、両者の平均として頭蓋内容積を約1200 mLとすると、潅流血流量は、1200 mL/min ＝20 mL/sec程度と考えられるため、上記計算値よりさらに温度上昇は少ないと考えられる。
Furthermore, in reality, there is perfusion throughout the brain tissue, and the intracranial volume is on average 1260 mL (1050-1500 mL) in men and 1130 mL (950-1400 mL) in women, so the average intracranial volume for both men is If the internal volume is approximately 1200 mL, the perfusion blood flow is thought to be approximately 1200 mL/min = 20 mL/sec, so the temperature rise is thought to be even smaller than the calculated value above.
また、過渡応答時の最大温度上昇（オーバーシュートOS）については、脳の減衰係数（k） = 0.6（0.5-0.7）であることから、ワーストケースとしてk = 0.5として計算すると、
OS = exp（-πk/(1-k2)1/2）
= exp（-3.14×0.5/(1-0.52)1/2）
= exp（-3.14×0.5/0.866）
= exp（-1.8138）= 0.1630 ℃ (< 1℃)
であり、さらにこのワーストケースのさらに2倍値であるk = 0.25としても
OS = exp（-πk/(1-k2)1/2）
= exp（-3.14×0.5/(1-0.252)1/2）
= exp（-3.14×0.5/0.968）
= exp（-1.6227）= 0.197 ℃ (< 1℃)
であり、上記と同様、組織温度上昇は小さく、本発明の照射条件は安全と考えられる。 Also, regarding the maximum temperature rise during transient response (overshoot OS), since the brain's damping coefficient (k) = 0.6 (0.5-0.7), if calculated with k = 0.5 as the worst case,
OS = exp(-πk/(1-k 2 ) 1/2 )
= exp(-3.14×0.5/(1-0.5 2 ) 1/2 )
=exp(-3.14×0.5/0.866)
= exp(-1.8138) = 0.1630℃ (< 1℃)
And even if we further double this worst case value, k = 0.25, OS = exp(-πk/(1-k 2 ) 1/2 )
= exp(-3.14×0.5/(1-0.252) 1/2 )
=exp(-3.14×0.5/0.968)
= exp(-1.6227) = 0.197℃ (< 1℃)
As above, the tissue temperature increase is small, and the irradiation conditions of the present invention are considered safe.
OS = exp（-πk/(1-k2)1/2）
= exp（-3.14×0.5/(1-0.52)1/2）
= exp（-3.14×0.5/0.866）
= exp（-1.8138）= 0.1630 ℃ (< 1℃)
であり、さらにこのワーストケースのさらに2倍値であるk = 0.25としても
OS = exp（-πk/(1-k2)1/2）
= exp（-3.14×0.5/(1-0.252)1/2）
= exp（-3.14×0.5/0.968）
= exp（-1.6227）= 0.197 ℃ (< 1℃)
であり、上記と同様、組織温度上昇は小さく、本発明の照射条件は安全と考えられる。 Also, regarding the maximum temperature rise during transient response (overshoot OS), since the brain's damping coefficient (k) = 0.6 (0.5-0.7), if calculated with k = 0.5 as the worst case,
OS = exp(-πk/(1-k 2 ) 1/2 )
= exp(-3.14×0.5/(1-0.5 2 ) 1/2 )
=exp(-3.14×0.5/0.866)
= exp(-1.8138) = 0.1630℃ (< 1℃)
And even if we further double this worst case value, k = 0.25, OS = exp(-πk/(1-k 2 ) 1/2 )
= exp(-3.14×0.5/(1-0.252) 1/2 )
=exp(-3.14×0.5/0.968)
= exp(-1.6227) = 0.197℃ (< 1℃)
As above, the tissue temperature increase is small, and the irradiation conditions of the present invention are considered safe.
実施例２：素子直下の組織の発熱
素子表面でのISPTAはハイドロフォン法による測定結果より、
10 mW/cm2 ×3.5 2 / 1.5 2 = 54.4 mW/cm2である。
1.6 cmのビーム幅で ISPTA = 200 mW/cm2、120秒照射で1.4℃温度上昇がみられることから（Abramowicz JS et al., J Ultrasound Med. 27,541-59, 2008.）、
(54.4 mW/cm2) ×1.4 ℃ / (200 mW/cm2) /2 min ＝ 0.19 ℃/min
20分間の照射によって 0.19 ℃/min×20 min = 3.8 ℃
温度上昇すると推定される。 Example 2: Heat generation in the tissue directly under the element ISPTA on the element surface is determined from the results of measurement using the hydrophone method.
10 mW/cm 2 ×3.5 2 / 1.5 2 = 54.4 mW/cm 2 .
With a beam width of 1.6 cm, ISPTA = 200 mW/cm 2 , and a temperature increase of 1.4°C after 120 seconds of irradiation (Abramowicz JS et al., J Ultrasound Med. 27,541-59, 2008.)
(54.4 mW/cm 2 ) ×1.4 ℃ / (200 mW/cm 2 ) /2 min = 0.19 ℃/min
0.19 ℃/min×20 min = 3.8 ℃ by irradiation for 20 minutes
It is estimated that the temperature will rise.
素子表面でのISPTAはハイドロフォン法による測定結果より、
10 mW/cm2 ×3.5 2 / 1.5 2 = 54.4 mW/cm2である。
1.6 cmのビーム幅で ISPTA = 200 mW/cm2、120秒照射で1.4℃温度上昇がみられることから（Abramowicz JS et al., J Ultrasound Med. 27,541-59, 2008.）、
(54.4 mW/cm2) ×1.4 ℃ / (200 mW/cm2) /2 min ＝ 0.19 ℃/min
20分間の照射によって 0.19 ℃/min×20 min = 3.8 ℃
温度上昇すると推定される。 Example 2: Heat generation in the tissue directly under the element ISPTA on the element surface is determined from the results of measurement using the hydrophone method.
10 mW/cm 2 ×3.5 2 / 1.5 2 = 54.4 mW/cm 2 .
With a beam width of 1.6 cm, ISPTA = 200 mW/cm 2 , and a temperature increase of 1.4°C after 120 seconds of irradiation (Abramowicz JS et al., J Ultrasound Med. 27,541-59, 2008.)
(54.4 mW/cm 2 ) ×1.4 ℃ / (200 mW/cm 2 ) /2 min = 0.19 ℃/min
0.19 ℃/min×20 min = 3.8 ℃ by irradiation for 20 minutes
It is estimated that the temperature will rise.
一般に、理論上42 ℃以上に長時間さらされると低温やけどを生じる可能性があるが、素子直下の皮膚の推定温度は平熱を37℃すると、
37.0 ℃ + 3.8 ℃＝40.8 ℃
であり、その可能性は低いと考えられる。さらに、頭全体への熱の拡散、潅流血流による拡散した熱の放熱を考慮すると、温度上昇は上記計算値よりさらに少ないと考えられる。 In general, it is theoretically possible to cause low-temperature burns if exposed to temperatures above 42 degrees Celsius, but the estimated temperature of the skin directly under the device is 37 degrees Celsius above normal temperature.
37.0℃ + 3.8℃＝40.8℃
Therefore, the possibility of this happening is considered to be low. Furthermore, considering the diffusion of heat throughout the head and the radiation of the diffused heat due to perfusion blood flow, the temperature increase is considered to be even smaller than the above calculated value.
37.0 ℃ + 3.8 ℃＝40.8 ℃
であり、その可能性は低いと考えられる。さらに、頭全体への熱の拡散、潅流血流による拡散した熱の放熱を考慮すると、温度上昇は上記計算値よりさらに少ないと考えられる。 In general, it is theoretically possible to cause low-temperature burns if exposed to temperatures above 42 degrees Celsius, but the estimated temperature of the skin directly under the device is 37 degrees Celsius above normal temperature.
37.0℃ + 3.8℃＝40.8℃
Therefore, the possibility of this happening is considered to be low. Furthermore, considering the diffusion of heat throughout the head and the radiation of the diffused heat due to perfusion blood flow, the temperature increase is considered to be even smaller than the above calculated value.
尚、凸型トランスデューサーが接触する直下組織の温度上昇には素子自体の発熱も影響するため、使用前、5分間のインターバル時には氷水に浸すなど素子自体を冷却する対策をとれば良い。
Furthermore, since the heat generated by the element itself also affects the rise in temperature of the tissue directly below which the convex transducer comes into contact, it is advisable to take measures to cool the element itself, such as by immersing it in ice water for 5 minutes before use.
上記より、拡散型超音波照射による発熱に関しては、皮膚直下、および脳組織のいずれにおいても臨床上無視できる範囲であると考えられる。
From the above, it is thought that the heat generation caused by diffused ultrasound irradiation is within a clinically negligible range both directly under the skin and in the brain tissue.
実施例３：臨床試験(軽度ＡＤ、MCI)によるLIPUS治療の効果検証
Example 3: Verification of the effectiveness of LIPUS treatment through clinical trial (mild AD, MCI)
３－１．ＬＩＰＵＳ照射条件
本試験においては、振動子部の直径を42mmとする円筒状の凸型トランスデューサーを使用し、図１０（Ａ）に示される、以下を含む照射条件を採用した。 3-1. LIPUS Irradiation Conditions In this test, a cylindrical convex transducer with a transducer portion having a diameter of 42 mm was used, and the irradiation conditions shown in FIG. 10(A) including the following were adopted.
本試験においては、振動子部の直径を42mmとする円筒状の凸型トランスデューサーを使用し、図１０（Ａ）に示される、以下を含む照射条件を採用した。 3-1. LIPUS Irradiation Conditions In this test, a cylindrical convex transducer with a transducer portion having a diameter of 42 mm was used, and the irradiation conditions shown in FIG. 10(A) including the following were adopted.
照射条件：
送信周波数：0.5 MHz
素子直下の音圧：1.3 MPa
パルス当たりサイクル数（波数）：32 cycle
PRT：1.28ミリ秒
超音波強度（ISPTA）：250mW/cm2 Irradiation conditions:
Transmission frequency: 0.5MHz
Sound pressure directly below the element: 1.3 MPa
Number of cycles per pulse (wave number): 32 cycle
PRT: 1.28ms Ultrasonic intensity (ISPTA): 250mW/ cm2
送信周波数：0.5 MHz
素子直下の音圧：1.3 MPa
パルス当たりサイクル数（波数）：32 cycle
PRT：1.28ミリ秒
超音波強度（ISPTA）：250mW/cm2 Irradiation conditions:
Transmission frequency: 0.5MHz
Sound pressure directly below the element: 1.3 MPa
Number of cycles per pulse (wave number): 32 cycle
PRT: 1.28ms Ultrasonic intensity (ISPTA): 250mW/ cm2
３－２．試験方法
本試験は、東北大学医学部附属病院の治験審査委員会(第173008号)により承認され、UMIN Trial ID:UMIN000033071として登録された。本試験は、ロールイン試験とランダム化比較(RCT)試験の2つの試験で構成された。ロールイン試験では、LIPUS治療の安全性はオープンな方法で対処され、RCT試験では、治療の有効性および安全性は、無作為化二重盲検プラセボ対照の方法で対処された。 3-2. Test method This study was approved by the Institutional Review Board of Tohoku University Hospital (No. 173008) and registered as UMIN Trial ID: UMIN000033071. This study consisted of two trials: a roll-in trial and a randomized controlled trial (RCT). In the roll-in trial, the safety of LIPUS treatment was addressed in an open manner, and in the RCT trial, the efficacy and safety of the treatment were addressed in a randomized, double-blind, placebo-controlled manner.
本試験は、東北大学医学部附属病院の治験審査委員会(第173008号)により承認され、UMIN Trial ID:UMIN000033071として登録された。本試験は、ロールイン試験とランダム化比較(RCT)試験の2つの試験で構成された。ロールイン試験では、LIPUS治療の安全性はオープンな方法で対処され、RCT試験では、治療の有効性および安全性は、無作為化二重盲検プラセボ対照の方法で対処された。 3-2. Test method This study was approved by the Institutional Review Board of Tohoku University Hospital (No. 173008) and registered as UMIN Trial ID: UMIN000033071. This study consisted of two trials: a roll-in trial and a randomized controlled trial (RCT). In the roll-in trial, the safety of LIPUS treatment was addressed in an open manner, and in the RCT trial, the efficacy and safety of the treatment were addressed in a randomized, double-blind, placebo-controlled manner.
選択基準のうちADの初期段階(ADによるMCIおよび軽度ＡＤ)の診断は、同意取得時にDSM-5による軽度アルツハイマー型認知症又は軽度認知障害の診断基準に適合し、かつNIA/AA診断基準の「probable Alzheimer’s disease」又は「MCI due to Alzheimer’s disease」に適合する患者とした。また、スクリーニング時にCDR(the Clinical Dementia Rating global score) 0.5～1.0、スクリーニング時にMMSE-J（the Japanese version of Mini Mental State Examination)スコアが20を超える患者も含まれていた。
Among the selection criteria, a diagnosis of early stages of AD (MCI due to AD and mild AD) must meet the diagnostic criteria for mild Alzheimer's dementia or mild cognitive impairment according to DSM-5 at the time of consent acquisition, and meet the NIA/AA diagnostic criteria. Patients were considered to be ``probable Alzheimer's disease'' or ``MCI due to Alzheimer's disease.'' Patients with a CDR (Clinical Dementia Rating global score) of 0.5 to 1.0 at screening and an MMSE-J (Japanese version of Mini Mental State Examination) score of >20 at screening were also included.
主要な除外基準は下記の通りである。（１）LIPUS治療または脳MRI検査を受けることができないこと、（２）登録時にGCS(Glasgow Coma Scale)スコアが12点以下の意識障害を有する患者、（３）12週間以内の症候性の脳梗塞または脳出血、（４）登録時に、頭部MRI検査にて微小出血が4ヶ所以上認められている患者、（５）重度の精神疾患患者。除外基準を有さずに組み入れ基準を満たした両性の患者を50～90歳で本試験に登録した。
The main exclusion criteria are as follows. (1) Inability to undergo LIPUS treatment or brain MRI examination, (2) Patients with impaired consciousness with a GCS (Glasgow Coma Scale) score of 12 points or less at the time of enrollment, (3) Symptomatic brain disease within 12 weeks. Infarction or cerebral hemorrhage; (4) patients with 4 or more microbleeds detected on head MRI at the time of enrollment; (5) patients with severe mental illness. Patients of both sexes who met the inclusion criteria and had no exclusion criteria were enrolled in the study between the ages of 50 and 90.
３－３．ＬＩＰＵＳ治療
LIPUS治療は、東北大学医学部附属病院の1施設で、LIPUS治療の装置に精通した医師によって行われた。LIPUSは、図５に示すようにヘッドセットにより両側頭骨にそれぞれ固定された凸型トランスデューサーを用いて脳全体に対して照射した。LIPUS治療は以下の治療プロトコルにしたがって実施した。 3-3. LIPUS treatment LIPUS treatment was performed at a facility at Tohoku University Hospital, by a doctor familiar with LIPUS treatment equipment. As shown in Figure 5, LIPUS irradiated the entire brain using convex transducers fixed to both temporal bones using a headset. LIPUS treatment was performed according to the following treatment protocol.
LIPUS治療は、東北大学医学部附属病院の1施設で、LIPUS治療の装置に精通した医師によって行われた。LIPUSは、図５に示すようにヘッドセットにより両側頭骨にそれぞれ固定された凸型トランスデューサーを用いて脳全体に対して照射した。LIPUS治療は以下の治療プロトコルにしたがって実施した。 3-3. LIPUS treatment LIPUS treatment was performed at a facility at Tohoku University Hospital, by a doctor familiar with LIPUS treatment equipment. As shown in Figure 5, LIPUS irradiated the entire brain using convex transducers fixed to both temporal bones using a headset. LIPUS treatment was performed according to the following treatment protocol.
治療プロトコル(図１０（Ｂ）)：
１日治療：1回の照射時間：20分間±1分にて、毎回5分間以上の間隔をおいて3回行った。
１セッション(LIPUS×3）：１日治療を、１週間に３回、1日おきに行った。
セッション数：１セッションを12週間毎に６セッション行った（0、12、24、36、48、60週目）。 Treatment protocol (Figure 10(B)):
One day treatment: One irradiation time: 20 minutes ± 1 minute, three times with an interval of 5 minutes or more each time.
1 session (LIPUS x 3): 1 day treatment was performed 3 times a week, every other day.
Number of sessions: 1 session was conducted every 12 weeks for 6 sessions ( weeks 0, 12, 24, 36, 48, and 60).
１日治療：1回の照射時間：20分間±1分にて、毎回5分間以上の間隔をおいて3回行った。
１セッション(LIPUS×3）：１日治療を、１週間に３回、1日おきに行った。
セッション数：１セッションを12週間毎に６セッション行った（0、12、24、36、48、60週目）。 Treatment protocol (Figure 10(B)):
One day treatment: One irradiation time: 20 minutes ± 1 minute, three times with an interval of 5 minutes or more each time.
1 session (LIPUS x 3): 1 day treatment was performed 3 times a week, every other day.
Number of sessions: 1 session was conducted every 12 weeks for 6 sessions (
ロールイン試験では、LIPUS治療は、素子直下音圧(MPa)を0.5(N=1)から1.0(N=2)、および1.3(N=2)に増加させた条件下で入院中の1セッションに対して実施し、周波数(0.5MHz)、サイクル数(32)、およびパルス反復周波数(PRF)(781Hz)を固定した。予備実験に基づき、側頭骨の厚さの違いによる超音波伝達の減衰を低減するために、LIPUS周波数をマウスの1.875MHzからヒトの0.5MHzに変更した。ロールイン試験では患者を12週間追跡調査した。RCT試験では、患者を無作為に2群に分け、外来にて3ヶ月間隔で18ヶ月間に6セッションにわたってLIPUSまたはプラセボ治療のいずれかを受けた(図１０)。試験の間、患者と認知機能検査を行った担当医師は治療のために盲検化され、治療の鍵を知っていたのは治療医だけであった。RCT試験におけるLIPUS治療の条件は以下の通りとした。周波数0.5MHz、素子直下音圧1.3MPa、サイクル数32、パルス繰り返し周波数(PRF)781Hz、パルス繰り返し周期(PRT)1.28msec(図１０)、ISPTA=250mW/cm2。
In the roll-in study, LIPUS treatment was performed for one session during hospitalization under conditions where the sound pressure (MPa) directly below the element was increased from 0.5 (N = 1) to 1.0 (N = 2) and 1.3 (N = 2). The frequency (0.5MHz), number of cycles (32), and pulse repetition frequency (PRF) (781Hz) were fixed. Based on preliminary experiments, the LIPUS frequency was changed from 1.875MHz in mice to 0.5MHz in humans to reduce the attenuation of ultrasound transmission due to differences in temporal bone thickness. In the roll-in study, patients were followed for 12 weeks. In the RCT study, patients were randomly divided into two groups and received either LIPUS or placebo treatment for 6 sessions over 18 months, spaced 3 months apart in an outpatient setting (Figure 10). During the trial, the patients and their physicians who administered the cognitive tests were blinded to the treatment, with only the treating physician knowing the key to treatment. The conditions for LIPUS treatment in the RCT study were as follows. Frequency: 0.5MHz, sound pressure directly below the element: 1.3MPa, number of cycles: 32, pulse repetition frequency (PRF): 781Hz, pulse repetition period (PRT): 1.28msec (Figure 10), ISPTA=250mW/cm 2 .
３－４．評価項目
有効性のエンドポイントは、ロールイン試験においてはLIPUS治療装置のユーザビリティであった。RCTプロトコルにおいて、主要な有効性エンドポイントは、初回治療後72週におけるADAS-J cog合計点の変化量であった。副次的有効性評価項目には、初回治療後24、48週におけるADAS-J cog合計点の変化量、初回治療後24、48、72週におけるADAS-J cogレスポンダーの割合、および初回治療後24、48、72週におけるCDR sum of boxes総合点の変化量などが含まれていた。LIPUS治療のレスポンダーは、ADAS-Jcog合計が増加しなかった(ベースラインからの悪化もしくは改善がない)患者として定義した。ベースラインからのADAS-Jcogスコアの0点以上の改善、4点以上の改善、7点以上の改善、および10点以上の改善をカウントおよびパーセンテージとして提示した。p値<0.05は統計的に有意であると考えた。 3-4. Evaluation Items The efficacy endpoint was the usability of the LIPUS treatment device in the roll-in study. In the RCT protocol, the primary efficacy endpoint was change in ADAS-J cogtotal score 72 weeks after initial treatment. Secondary efficacy endpoints include change in ADAS-J cog total score at weeks 24 and 48 after initial treatment, proportion of ADAS-J cog responders at weeks 24, 48, and 72 after initial treatment, and This included the amount of change in CDR sum of boxes at weeks 24, 48, and 72. Responders to LIPUS treatment were defined as patients whose ADAS-Jcog total did not increase (no worsening or no improvement from baseline). Improvements in ADAS-Jcog scores from baseline of 0 points or more, 4 or more points, 7 or more points, and 10 or more points were presented as counts and percentages. A p value <0.05 was considered statistically significant.
有効性のエンドポイントは、ロールイン試験においてはLIPUS治療装置のユーザビリティであった。RCTプロトコルにおいて、主要な有効性エンドポイントは、初回治療後72週におけるADAS-J cog合計点の変化量であった。副次的有効性評価項目には、初回治療後24、48週におけるADAS-J cog合計点の変化量、初回治療後24、48、72週におけるADAS-J cogレスポンダーの割合、および初回治療後24、48、72週におけるCDR sum of boxes総合点の変化量などが含まれていた。LIPUS治療のレスポンダーは、ADAS-Jcog合計が増加しなかった(ベースラインからの悪化もしくは改善がない)患者として定義した。ベースラインからのADAS-Jcogスコアの0点以上の改善、4点以上の改善、7点以上の改善、および10点以上の改善をカウントおよびパーセンテージとして提示した。p値<0.05は統計的に有意であると考えた。 3-4. Evaluation Items The efficacy endpoint was the usability of the LIPUS treatment device in the roll-in study. In the RCT protocol, the primary efficacy endpoint was change in ADAS-J cog
安全性評価項目については、ロールイン試験では、LIPUS治療後12週目のMRI所見と4週目、8週目、12週目の症状とした。RCT試験では、安全性エンドポイントには、試験中の症状および有害作用、および72週時点のMRI所見が含まれていた。
Regarding safety evaluation items, in the roll-in study, MRI findings at 12 weeks after LIPUS treatment and symptoms at 4, 8, and 12 weeks were used. In RCT trials, safety endpoints included symptoms and adverse effects during the study and MRI findings at 72 weeks.
３－５．早期終了
ロールインプロトコルは、予定通り2018年5月から2019年3月までに5人の患者で完了した(図１１)。しかし、RCT試験では、COVID-19のパンデミックの影響により組入れを途中で中止した状況が生じ、予定患者数は40名であったが、PMDA(独立行政法人医薬品医療機器総合機構)の承認を得て、2019年4月から2020年8月まで、最終22名の患者数で早期に終了した(図１１)。 3-5. Early completion The roll-in protocol was completed on schedule in five patients from May 2018 to March 2019 (Figure 11). However, in the RCT trial, enrollment was stopped midway due to the impact of the COVID-19 pandemic, and although the planned number of patients was 40, the trial did not receive approval from the Pharmaceuticals and Medical Devices Agency (PMDA). The trial ended early with a final number of 22 patients from April 2019 to August 2020 (Figure 11).
ロールインプロトコルは、予定通り2018年5月から2019年3月までに5人の患者で完了した(図１１)。しかし、RCT試験では、COVID-19のパンデミックの影響により組入れを途中で中止した状況が生じ、予定患者数は40名であったが、PMDA(独立行政法人医薬品医療機器総合機構)の承認を得て、2019年4月から2020年8月まで、最終22名の患者数で早期に終了した(図１１)。 3-5. Early completion The roll-in protocol was completed on schedule in five patients from May 2018 to March 2019 (Figure 11). However, in the RCT trial, enrollment was stopped midway due to the impact of the COVID-19 pandemic, and although the planned number of patients was 40, the trial did not receive approval from the Pharmaceuticals and Medical Devices Agency (PMDA). The trial ended early with a final number of 22 patients from April 2019 to August 2020 (Figure 11).
３－６．Ｒｏｌｌ－ｉｎ試験結果
ロールイン試験では、有害作用は認められなかった。5人の患者(男性4人、女性1人)は70.8±9.5歳で、軽度ＡＤ１人とADによるMCI4人で、MMSE-Jスコアは24.8±3.4であった。治療から12週間後、副作用や異常なMRI所見は認められなかった。 3-6. Roll-in test results No adverse effects were observed in the roll-in test. Five patients (4 men, 1 woman) were 70.8 ± 9.5 years old, 1 with mild AD and 4 with MCI due to AD, and the MMSE-J score was 24.8 ± 3.4. After 12 weeks of treatment, no side effects or abnormal MRI findings were observed.
ロールイン試験では、有害作用は認められなかった。5人の患者(男性4人、女性1人)は70.8±9.5歳で、軽度ＡＤ１人とADによるMCI4人で、MMSE-Jスコアは24.8±3.4であった。治療から12週間後、副作用や異常なMRI所見は認められなかった。 3-6. Roll-in test results No adverse effects were observed in the roll-in test. Five patients (4 men, 1 woman) were 70.8 ± 9.5 years old, 1 with mild AD and 4 with MCI due to AD, and the MMSE-J score was 24.8 ± 3.4. After 12 weeks of treatment, no side effects or abnormal MRI findings were observed.
３－７．ＲＣＴ試験結果
RCT試験では、プラセボ群では24週、48週、72週で認知機能が徐々に悪化したが、LIPUS群では認知機能悪化が抑制される傾向が示された(図１２－１３、P=0.257)。副作用は認められなかった。 3-7. RCT study results In the RCT study, cognitive function gradually deteriorated in the placebo group at 24, 48, and 72 weeks, but cognitive function deterioration tended to be suppressed in the LIPUS group (Figures 12-13, P =0.257). No side effects were observed.
RCT試験では、プラセボ群では24週、48週、72週で認知機能が徐々に悪化したが、LIPUS群では認知機能悪化が抑制される傾向が示された(図１２－１３、P=0.257)。副作用は認められなかった。 3-7. RCT study results In the RCT study, cognitive function gradually deteriorated in the placebo group at 24, 48, and 72 weeks, but cognitive function deterioration tended to be suppressed in the LIPUS group (Figures 12-13, P =0.257). No side effects were observed.
（１）ADAS-J cog合計点の変化量
試験に登録された22人の患者のうち、4人は計画されたプロトコルを完了しなかった(図１１)。別の3人の患者は、試験の早期終了のために4つのセッションを完了した。したがって、合計19人の患者が有効性について分析され、18人の患者が安全性について分析された(図１１)。各患者の臨床特性を下記表１に示す。LIPUS群とプラセボ群との間に臨床的特徴または認知機能に有意差はなかった。安全性の問題については、脳MRI所見を含むLIPUS治療の有害作用はなかった。 (1) Amount of change in ADAS-J cog total score Of the 22 patients enrolled in the study, 4 did not complete the planned protocol (Figure 11). Another three patients completed four sessions due to early termination of the study. Therefore, a total of 19 patients were analyzed for efficacy and 18 patients for safety (Figure 11). The clinical characteristics of each patient are shown in Table 1 below. There were no significant differences in clinical characteristics or cognitive function between the LIPUS and placebo groups. Regarding safety issues, there were no adverse effects of LIPUS treatment, including brain MRI findings.
試験に登録された22人の患者のうち、4人は計画されたプロトコルを完了しなかった(図１１)。別の3人の患者は、試験の早期終了のために4つのセッションを完了した。したがって、合計19人の患者が有効性について分析され、18人の患者が安全性について分析された(図１１)。各患者の臨床特性を下記表１に示す。LIPUS群とプラセボ群との間に臨床的特徴または認知機能に有意差はなかった。安全性の問題については、脳MRI所見を含むLIPUS治療の有害作用はなかった。 (1) Amount of change in ADAS-J cog total score Of the 22 patients enrolled in the study, 4 did not complete the planned protocol (Figure 11). Another three patients completed four sessions due to early termination of the study. Therefore, a total of 19 patients were analyzed for efficacy and 18 patients for safety (Figure 11). The clinical characteristics of each patient are shown in Table 1 below. There were no significant differences in clinical characteristics or cognitive function between the LIPUS and placebo groups. Regarding safety issues, there were no adverse effects of LIPUS treatment, including brain MRI findings.
主要評価項目（図１２）：
初回の治療後72週のADAS-J cog合計点のベースラインからの変化量について、LIPUS群のベースラインからの変化量の平均値は0.64（95%信頼区間-2.84～4.12）であり、プラセボ群のベースラインからの変化量の平均値は3.78（95%信頼区間-0.67～8.23）であった。
また、平均値の群間差は-3.14（95%信頼区間-8.79～2.51）であり、プラセボ群と比較してLIPUS群においてADAS-J cogの得点に改善傾向が認められた。 Primary endpoint (Figure 12):
Regarding the change from baseline in ADAS-J cogtotal score 72 weeks after the first treatment, the mean change from baseline in the LIPUS group was 0.64 (95% confidence interval -2.84 to 4.12), compared with placebo. The mean change from baseline for the group was 3.78 (95% confidence interval -0.67 to 8.23).
Furthermore, the difference between the groups in the mean value was -3.14 (95% confidence interval -8.79 to 2.51), indicating a trend toward improvement in ADAS-J cog scores in the LIPUS group compared to the placebo group.
初回の治療後72週のADAS-J cog合計点のベースラインからの変化量について、LIPUS群のベースラインからの変化量の平均値は0.64（95%信頼区間-2.84～4.12）であり、プラセボ群のベースラインからの変化量の平均値は3.78（95%信頼区間-0.67～8.23）であった。
また、平均値の群間差は-3.14（95%信頼区間-8.79～2.51）であり、プラセボ群と比較してLIPUS群においてADAS-J cogの得点に改善傾向が認められた。 Primary endpoint (Figure 12):
Regarding the change from baseline in ADAS-J cog
Furthermore, the difference between the groups in the mean value was -3.14 (95% confidence interval -8.79 to 2.51), indicating a trend toward improvement in ADAS-J cog scores in the LIPUS group compared to the placebo group.
副次評価項目 (図１３、下記表２、３)：
LIPUS群では変化量に大きな変動は認めなかったが、プラセボ群においては変化量の経時的な上昇が認められた。LIPUS群とプラセボ群の平均値の群間差は、24週時点で-0.61（95%信頼区間-4.72～3.49）、48週時点で-1.60（95%信頼区間-6.81～3.62）、72週時点で-3.14（95%信頼区間-8.79～2.51）であり、プラセボ群と比較してLIPUS群においてADAS-J cogの得点に改善傾向が認められた。改善傾向は治療を６セッション行った７２週時点が特に大きかった。 Secondary endpoints (Figure 13, Tables 2 and 3 below):
In the LIPUS group, no major changes were observed in the amount of change, but in the placebo group, an increase in the amount of change over time was observed. The difference in mean values between the LIPUS group and the placebo group was -0.61 (95% CI -4.72 to 3.49) at 24 weeks, -1.60 (95% CI -6.81 to 3.62) at 48 weeks, and -1.60 (95% CI -6.81 to 3.62) at 72 weeks. -3.14 (95% confidence interval -8.79 to 2.51) at time point, indicating a trend towards improvement in ADAS-J cog scores in the LIPUS group compared to the placebo group. The trend toward improvement was particularly strong atweek 72, after six sessions of treatment.
LIPUS群では変化量に大きな変動は認めなかったが、プラセボ群においては変化量の経時的な上昇が認められた。LIPUS群とプラセボ群の平均値の群間差は、24週時点で-0.61（95%信頼区間-4.72～3.49）、48週時点で-1.60（95%信頼区間-6.81～3.62）、72週時点で-3.14（95%信頼区間-8.79～2.51）であり、プラセボ群と比較してLIPUS群においてADAS-J cogの得点に改善傾向が認められた。改善傾向は治療を６セッション行った７２週時点が特に大きかった。 Secondary endpoints (Figure 13, Tables 2 and 3 below):
In the LIPUS group, no major changes were observed in the amount of change, but in the placebo group, an increase in the amount of change over time was observed. The difference in mean values between the LIPUS group and the placebo group was -0.61 (95% CI -4.72 to 3.49) at 24 weeks, -1.60 (95% CI -6.81 to 3.62) at 48 weeks, and -1.60 (95% CI -6.81 to 3.62) at 72 weeks. -3.14 (95% confidence interval -8.79 to 2.51) at time point, indicating a trend towards improvement in ADAS-J cog scores in the LIPUS group compared to the placebo group. The trend toward improvement was particularly strong at
主要評価項目である2群間の72週目におけるADAS-Jcogスコアの差は、患者数が少ないため統計的に有意な水準(P=0.257)に達しなかったが、各群の58人以上の症例数であれば、統計的に有意なレベルに達すると予測された。
The primary endpoint, the difference in ADAS-Jcog score at week 72 between the two groups, did not reach a statistically significant level (P=0.257) due to the small number of patients; It was predicted that the number of cases would reach a statistically significant level.
AD治療薬として注目されているAducanumabを投与した患者群においては、ADAS-Jcog 合計点のベースラインからの変化量は漸増しながら推移することが確認されている（Samantha B. H. et al, 「EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease」April 2020; https://investors.biogen.com/static-files/f91e95d9-2fce-46ce-9115-0628cfe96e83?msclkid=91ceb2e6a65b11ec846427ccddd0ab57(2022年4月時点)）。今回、LIPUS群において確認された上記変化量の値の推移は、本治療プログラムが当該治療薬と同等またはそれ以上の優れた認知機能改善効果を奏することを示唆している。
In a group of patients treated with Aducanumab, which is attracting attention as an AD treatment drug, it has been confirmed that the change in ADAS-Jcog total score from baseline increases gradually (Samantha B. H. et al. “EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer's Disease” April 2020; https://investors.biogen.com/static-files/f91e95d9-2fce-46ce-9115-0628cfe96e8 3?msclkid= 91ceb2e6a65b11ec846427ccddd0ab57 (as of April 2022). The changes in the above-mentioned changes observed in the LIPUS group suggest that this treatment program has an effect on cognitive function that is equivalent to or better than that of the therapeutic drug.
（２）初回治療後24、48、72週におけるADAS-J cogレスポンダーの割合
ベースラインから72週目まで悪化のないレスポンダーの有病率は、LIPUS群では50%(5/10)であったが、プラセボ群では0%(0/5)であり、認知機能の改善を伴うレスポンダーの有病率はLIPUS群でのみ漸進的に増加した(図１４、下記表４）。 (2) Proportion of ADAS-J cog responders at 24, 48, and 72 weeks after initial treatment The prevalence of non-deteriorating responders from baseline toweek 72 was 50% (5/10) in the LIPUS group. However, it was 0% (0/5) in the placebo group, and the prevalence of responders with improved cognitive function gradually increased only in the LIPUS group (Figure 14, Table 4 below).
ベースラインから72週目まで悪化のないレスポンダーの有病率は、LIPUS群では50%(5/10)であったが、プラセボ群では0%(0/5)であり、認知機能の改善を伴うレスポンダーの有病率はLIPUS群でのみ漸進的に増加した(図１４、下記表４）。 (2) Proportion of ADAS-J cog responders at 24, 48, and 72 weeks after initial treatment The prevalence of non-deteriorating responders from baseline to
初回治療後48、72週において、レスポンダーはLIPUS群にのみ確認された。また、LIPUS群において、変化量の減少が比較的大きなレスポンダーは、経時的に増加することが確認された。この結果は、本治療プログラムを継続して行うことにより、認知機能の漸進的な改善が期待できることを示す。
At 48 and 72 weeks after the initial treatment, responders were confirmed only in the LIPUS group. Additionally, in the LIPUS group, it was confirmed that responders with a relatively large decrease in the amount of change increased over time. These results indicate that by continuing this treatment program, gradual improvement in cognitive function can be expected.
ADAS-Jcog総和の変化（図１２－１３）およびADAS-Jcogレスポンダーの有病率の推移（図１４）において、プラセボ群に対するLIPUS群の治療効果は、24週、48週、72週と治療の進行と共に大きくなり、72週において最大となった。24週が２セッション、48週が４セッション、72週が６セッションの治療終了後３ヶ月時点で評価していることを考慮すると、６セッション以上のLIPUS治療が望ましい。
In terms of changes in the ADAS-Jcog total (Figures 12-13) and trends in the prevalence of ADAS-Jcog responders (Figure 14), the treatment effect of the LIPUS group compared to the placebo group was significant at 24 weeks, 48 weeks, and 72 weeks. It increased in size as the tumor progressed and reached its maximum at 72 weeks. Considering that the evaluation was performed 3 months after the completion of treatment with 2 sessions at 24 weeks, 4 sessions at 48 weeks, and 6 sessions at 72 weeks, LIPUS treatment with 6 or more sessions is desirable.
（３）ＡＤＡＳ－Ｊｃｏｇ：層別解析
小数例ではあるがADAS-Jcogのレスポンダーについて層別解析を検討した結果は下記の通りであった。 (3) ADAS-Jcog: Stratified analysis The results of stratified analysis of ADAS-Jcog responders, although only a small number of cases, are as follows.
小数例ではあるがADAS-Jcogのレスポンダーについて層別解析を検討した結果は下記の通りであった。 (3) ADAS-Jcog: Stratified analysis The results of stratified analysis of ADAS-Jcog responders, although only a small number of cases, are as follows.
１．responderとnon-responder間で、年齢、性別、身長、体重、既往歴の有無、住環境変化の有無 の偏りは見られない(服薬アドヒアランス及び家族構成の変化の有無は全員なしのため考慮せず)。合併症の有無については、高血圧の頻度に有意差が出ている。
1. No bias was observed between responders and non-responders in terms of age, gender, height, weight, medical history, and changes in living environment (medication adherence and changes in family structure were not taken into consideration as none of them were present). ). Regarding the presence or absence of complications, there was a significant difference in the frequency of hypertension.
２．responder、semi-responder及びnon-responderそれぞれで、全員が共通して使用している併用薬はない。
2. There are no concomitant medications commonly used by all responders, semi-responders, and non-responders.
３．responder及びnon-responderそれぞれで、全員が共通して行った併用療法はない。
3. There was no combination therapy that was common to all responders and non-responders.
４．responder、semi-responder及びnon-responderそれぞれで、全員に共通して共通して起きた有害事象はない。群間の重篤度、転帰の偏りもない。最も多い事象は高血圧で両群間に差がある。
4. There were no common adverse events that occurred among responders, semi-responders, and non-responders. There was no bias in severity or outcome between groups. The most common event was hypertension, with a difference between the two groups.
５．responder、semi-responder及びnon-responderで、機器不具合による偏りは見られない。
5. No bias due to equipment failure was observed among responders, semi-responders, and non-responders.
６．responder、semi-responder及びnon-responderそれぞれで、全員に共通して共通して起きた身体所見はない。responder、semi-responder及びnon-responderそれぞれで、全員が共通した既往歴、合併症はない。一番多い合併症は高血圧である。既往歴の重複は少ないが、前立腺がんが2例あった。
6. There were no common physical findings common to all responders, semi-responders, and non-responders. Responders, semi-responders, and non-responders each have no common medical history or complications. The most common complication is high blood pressure. Although there was little overlap in past medical history, there were two cases of prostate cancer.
高血圧がベースにある症例の方がResponderに多く見られたため、割合の比較として、χ二乗検定を実施した結果を下記表５に示す。
Because cases with underlying hypertension were more common in Responders, a chi-square test was performed to compare the proportions, and the results are shown in Table 5 below.
χ二乗検定の結果、p<0.05となり、有意差がついた。本結果は、高血圧がベースにあるAD患者にLIPUS治療が効きやすいかもしれないことを示唆している。
The result of the chi-square test was p<0.05, indicating a significant difference. These results suggest that LIPUS treatment may be more effective in AD patients with underlying hypertension.
（４）初回治療後24、48、72週におけるCDR sum of boxes総合点の変化量
図１５及び下記表６に、初回治療後２４、４８、７２週におけるCDR sum of boxes 総合点のベースラインからの変化量の経時的評価結果を示す。プラセボ群においては、その変化量の値は経時的に大きくなる傾向が認められた。一方、LIPUS群においては、その変化量の値は漸増するものの、いずれの時点においてもプラセボ群の値と比べて、低く維持され推移する傾向が認められた。この結果もまた、プラセボ群においては、認知機能が徐々に悪化していく傾向が認められたのに対して、LIPUS群においては、認知機能の悪化は抑制されながら推移し、認知機能が維持される傾向が認められたことを示す。 (4) Changes in the CDR sum of boxes total score at 24, 48, and 72 weeks after the initial treatment Figure 15 and Table 6 below show the changes from the baseline in the CDR sum of boxes total score at 24, 48, and 72 weeks after the initial treatment. The results of the evaluation of the amount of change over time are shown. In the placebo group, the value of the amount of change tended to increase over time. On the other hand, in the LIPUS group, although the value of the amount of change gradually increased, it tended to remain lower than the value in the placebo group at all time points. This result also showed that in the placebo group, there was a tendency for cognitive function to gradually deteriorate, whereas in the LIPUS group, the deterioration of cognitive function continued while being suppressed, and cognitive function was maintained. This indicates that there is a tendency to
図１５及び下記表６に、初回治療後２４、４８、７２週におけるCDR sum of boxes 総合点のベースラインからの変化量の経時的評価結果を示す。プラセボ群においては、その変化量の値は経時的に大きくなる傾向が認められた。一方、LIPUS群においては、その変化量の値は漸増するものの、いずれの時点においてもプラセボ群の値と比べて、低く維持され推移する傾向が認められた。この結果もまた、プラセボ群においては、認知機能が徐々に悪化していく傾向が認められたのに対して、LIPUS群においては、認知機能の悪化は抑制されながら推移し、認知機能が維持される傾向が認められたことを示す。 (4) Changes in the CDR sum of boxes total score at 24, 48, and 72 weeks after the initial treatment Figure 15 and Table 6 below show the changes from the baseline in the CDR sum of boxes total score at 24, 48, and 72 weeks after the initial treatment. The results of the evaluation of the amount of change over time are shown. In the placebo group, the value of the amount of change tended to increase over time. On the other hand, in the LIPUS group, although the value of the amount of change gradually increased, it tended to remain lower than the value in the placebo group at all time points. This result also showed that in the placebo group, there was a tendency for cognitive function to gradually deteriorate, whereas in the LIPUS group, the deterioration of cognitive function continued while being suppressed, and cognitive function was maintained. This indicates that there is a tendency to
３－８．安全性評価
（１）安全性評価項目
１)初回治験治療から観察期間終了時までに発生した、治験機器との因果関係が否定されないイベント（頭痛、頭重感、嘔気・嘔吐、不眠、ふらつき、四肢の脱力・麻痺、構語障害、歩行障害、皮膚熱傷、視力障害 、入院を要する全身状態の悪化、痙攣、頭蓋内出血、死亡 等）の発生頻度
２）頭部 MRI 検査（頭蓋内出血、脳浮腫、器質的障害、脳梗塞の有無）
３）有害事象
４）不具合 3-8. Safety evaluation (1) Safety evaluation items 1) Events that occur between the initial study treatment and the end of the observation period for which a causal relationship to the study device cannot be ruled out (headache, dizziness, nausea/vomiting, insomnia, light-headedness, 2) Frequency of head MRI (intracranial hemorrhage, cerebral edema, organic physical disorder, presence or absence of cerebral infarction)
3) Adverse events 4) Malfunctions
（１）安全性評価項目
１)初回治験治療から観察期間終了時までに発生した、治験機器との因果関係が否定されないイベント（頭痛、頭重感、嘔気・嘔吐、不眠、ふらつき、四肢の脱力・麻痺、構語障害、歩行障害、皮膚熱傷、視力障害 、入院を要する全身状態の悪化、痙攣、頭蓋内出血、死亡 等）の発生頻度
２）頭部 MRI 検査（頭蓋内出血、脳浮腫、器質的障害、脳梗塞の有無）
３）有害事象
４）不具合 3-8. Safety evaluation (1) Safety evaluation items 1) Events that occur between the initial study treatment and the end of the observation period for which a causal relationship to the study device cannot be ruled out (headache, dizziness, nausea/vomiting, insomnia, light-headedness, 2) Frequency of head MRI (intracranial hemorrhage, cerebral edema, organic physical disorder, presence or absence of cerebral infarction)
3) Adverse events 4) Malfunctions
（２）結果
LIPUS群で発生した有害事象（発現率（例数）・件数）は81.8%（9/11例）・26件であった。重篤な有害事象が2例認められ、その内訳は白内障1例、膝蓋骨骨折1例であった。因果関係はいずれも否定された。また、プラセボ群で発生した有害事象（発現率（例数）・件数）は75.0%（6/8例）・24件であり、重篤な有害事象の発現はなかった。 (2) Results The adverse events (incidence rate (number of cases)/number of cases) that occurred in the LIPUS group was 81.8% (9/11 cases), 26 events. Two serious adverse events were observed, including one case of cataract and one case of patella fracture. Any causal relationship was denied. In addition, the adverse events (incidence rate (number of cases)/number of cases) that occurred in the placebo group was 75.0% (6/8 cases), 24 events, and there were no serious adverse events.
LIPUS群で発生した有害事象（発現率（例数）・件数）は81.8%（9/11例）・26件であった。重篤な有害事象が2例認められ、その内訳は白内障1例、膝蓋骨骨折1例であった。因果関係はいずれも否定された。また、プラセボ群で発生した有害事象（発現率（例数）・件数）は75.0%（6/8例）・24件であり、重篤な有害事象の発現はなかった。 (2) Results The adverse events (incidence rate (number of cases)/number of cases) that occurred in the LIPUS group was 81.8% (9/11 cases), 26 events. Two serious adverse events were observed, including one case of cataract and one case of patella fracture. Any causal relationship was denied. In addition, the adverse events (incidence rate (number of cases)/number of cases) that occurred in the placebo group was 75.0% (6/8 cases), 24 events, and there were no serious adverse events.
以上の結果を要約すると、主要評価項目である初回投与72週におけるADAS-J cog合計点の変化量で、プラセボ群よりLIPUS群において良好な結果が示された。本発明における、凸型トランスデューサーによる非集束超音波エネルギーの照射条件及び治療プログラムは、「疾患修飾療法（Disease-modifying therapy）」として、既存の認知症治療薬に追加使用することが可能であり、早期ADに有効である可能性が示唆された。
To summarize the above results, the primary endpoint, the change in total ADAS-J cog score at 72 weeks after the first administration, showed better results in the LIPUS group than in the placebo group. The irradiation conditions and treatment program for unfocused ultrasound energy using a convex transducer according to the present invention can be used in addition to existing dementia treatment drugs as "disease-modifying therapy." , it was suggested that it may be effective for early AD.
主要評価項目の結果から本発明の治験方法はAducanumabによる治療成績と比較しても、６セッション以上の治療によりADAS-J cog合計点の変化量でより認知機能悪化を抑制できる可能性が示唆されており、症例数を増やした検証的試験の実施により、十分な有効性と有意差取得が期待できる。
The results of the primary endpoint suggest that the clinical trial method of the present invention may be able to suppress the deterioration of cognitive function more by the amount of change in ADAS-J cog total score when treated with 6 or more sessions, even when compared to the treatment results with Aducanumab. Therefore, sufficient efficacy and significant differences can be expected by conducting a confirmatory trial with an increased number of patients.
全体の結論：
軽度アルツハイマー型認知症及び軽度認知障害患者において、経頭蓋超音波治療装置を用いて低出力パルス波超音波（Low-intensity pulsed ultrasound：LIPUS）を照射することで、認知機能低下の抑制効果が認められた。また安全性に問題がないことが確認された。 Overall conclusion:
In patients with mild Alzheimer's dementia and mild cognitive impairment, irradiation of low-intensity pulsed ultrasound (LIPUS) using a transcranial ultrasound therapy device was found to be effective in suppressing cognitive decline. It was done. It was also confirmed that there were no safety issues.
軽度アルツハイマー型認知症及び軽度認知障害患者において、経頭蓋超音波治療装置を用いて低出力パルス波超音波（Low-intensity pulsed ultrasound：LIPUS）を照射することで、認知機能低下の抑制効果が認められた。また安全性に問題がないことが確認された。 Overall conclusion:
In patients with mild Alzheimer's dementia and mild cognitive impairment, irradiation of low-intensity pulsed ultrasound (LIPUS) using a transcranial ultrasound therapy device was found to be effective in suppressing cognitive decline. It was done. It was also confirmed that there were no safety issues.
前述したように、世界のＡＤ患者数は５，５００万人（２０１９年）にも上り、しかもその数は増加を続けており、その新たな治療法の開発は切望されている。従って、従来の薬物治療等とは異なる新たな認知症の治療方法を提供することができる本発明は、非常に有用なものである。
As mentioned above, the number of AD patients worldwide is as high as 55 million (2019), and this number continues to increase, and the development of new treatments is desperately needed. Therefore, the present invention, which can provide a new method for treating dementia that is different from conventional drug treatments, is extremely useful.
As mentioned above, the number of AD patients worldwide is as high as 55 million (2019), and this number continues to increase, and the development of new treatments is desperately needed. Therefore, the present invention, which can provide a new method for treating dementia that is different from conventional drug treatments, is extremely useful.
Claims (11)
- 認知症の患者を治療するための方法であって、
複数の凸型トランスデューサーと、凸型トランスデューサーに配置され、脳に非集束超音波エネルギーを伝達する超音波振動子と、凸型トランスデューサーに接続された超音波発生装置を用いて、凸型トランスデューサーに配置された超音波振動子から発生する非集束超音波エネルギーを患者の脳に伝達させる工程を含み、
前記工程が、前記複数の凸型トランスデューサーの間で前記非集束超音波エネルギーを順次照射し、
前記非集束超音波エネルギーの照射を以下の治療プログラムに従って行う方法：
治療プログラム
１回の照射時間：１～６０分
１日治療：１日当たり照射回数が１～４回
１セッション：１日治療を、５日から１０日間に１～７回行う
セッション数：１セッション治療を４週間～１６週間毎に継続的に繰り返し、６セッション以上行う。 A method for treating a patient with dementia, the method comprising:
Using multiple convex transducers, an ultrasound transducer placed on the convex transducer to transmit unfocused ultrasound energy to the brain, and an ultrasound generator connected to the convex transducer, the convex transmitting unfocused ultrasound energy generated from an ultrasound transducer disposed in a transducer to the patient's brain;
The step sequentially irradiates the unfocused ultrasound energy between the plurality of convex transducers,
A method of irradiating the unfocused ultrasound energy according to the following treatment program:
Treatment program Duration of one irradiation: 1 to 60 minutes Daily treatment: 1 to 4 irradiations per day 1 session: 1 day treatment, 1 to 7 times over 5 to 10 days Number of sessions: 1 session treatment Repeat this continuously every 4 to 16 weeks for 6 or more sessions. - 前記治療プログラムにおいて、１回の照射時間を１５～２５分程度とし、１日当たりの照射回数を２～３回とする、請求項１に記載の方法。 The method according to claim 1, wherein in the treatment program, each irradiation time is about 15 to 25 minutes, and the number of irradiations per day is 2 to 3 times.
- 前記治療プログラムにおいて、１セッションにつき１日治療を隔日で、３回／週にて行う、請求項１に記載の方法。 2. The method of claim 1, wherein the treatment program includes one day of treatment per session, every other day, three times per week.
- 前記治療プログラムにおいて、１セッション治療を８～１２週毎に行う、請求項１に記載の方法。 2. The method of claim 1, wherein the treatment program includes one session of treatment every 8 to 12 weeks.
- 前記非集束超音波エネルギーの照射を、送信周波数：０．１～０．８ＭＨｚにて行う、請求項１に記載の方法。 The method according to claim 1, wherein the irradiation of the unfocused ultrasound energy is performed at a transmission frequency of 0.1 to 0.8 MHz.
- 前記非集束超音波エネルギーの照射を、素子直下の音圧：０．１～１．５Ｍｐａにて行う、請求項１に記載の方法。 The method according to claim 1, wherein the irradiation of the unfocused ultrasonic energy is performed at a sound pressure directly below the element: 0.1 to 1.5 MPa.
- 前記非集束超音波エネルギーの照射を、１パルス当たりのサイクル数：１６～６４ｃｙｃｌｅにて行う、請求項１に記載の方法。 The method according to claim 1, wherein the irradiation of the unfocused ultrasound energy is performed at a number of cycles per pulse: 16 to 64 cycles.
- 前記非集束超音波エネルギーの照射を、パルス繰り返し周期（Pulse Repetition time；ＰＲＴ）：０．６～１．８ミリ秒にて行う、請求項１に記載の方法。 The method according to claim 1, wherein the irradiation of the unfocused ultrasound energy is performed at a pulse repetition time (PRT) of 0.6 to 1.8 milliseconds.
- 前記非集束超音波エネルギーの照射を、超音波強度（ＩＳＰＴＡ）：７２０ｍＷ／ｃｍ２以下にて行う、請求項１に記載の方法。 The method according to claim 1, wherein the irradiation of the unfocused ultrasound energy is performed at an ultrasound intensity (ISPTA) of 720 mW/ cm2 or less.
- 前記非集束超音波エネルギーの照射を、以下の条件にて行う、請求項１に記載の方法：
送信周波数：０．５ＭＨｚ
素子直下の音圧：１．３ＭＰａ
１パルス当たりのサイクル数：３２ｃｙｃｌｅ
ＰＲＴ：１．２８ミリ秒
ＩＳＰＴＡ：２５０ｍＷ／ｃｍ２。 The method according to claim 1, wherein the irradiation of the unfocused ultrasound energy is performed under the following conditions:
Transmission frequency: 0.5MHz
Sound pressure directly below the element: 1.3MPa
Number of cycles per pulse: 32 cycles
PRT: 1.28 ms ISPTA: 250 mW/cm 2 . - 前記認知症の患者が、軽度アルツハイマー型認知症、又は軽度認知障害の患者である、請求項１に記載の方法。
2. The method according to claim 1, wherein the dementia patient is a patient with mild Alzheimer's dementia or mild cognitive impairment.
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| PCT/JP2022/021968 WO2023233475A1 (en) | 2022-05-30 | 2022-05-30 | Method for treating dementia |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015192189A1 (en) * | 2014-06-20 | 2015-12-23 | The University Of Queensland | Neurodegenerative disease treatment |
| WO2018181991A1 (en) * | 2017-03-30 | 2018-10-04 | 国立大学法人東北大学 | Device for treating dementia, method for operating said device, and program |
| US20190184206A1 (en) * | 2016-10-16 | 2019-06-20 | Vibrato Medical, Inc. | Extracorporeal therapeutic ultrasound for promoting angiogenesis |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015192189A1 (en) * | 2014-06-20 | 2015-12-23 | The University Of Queensland | Neurodegenerative disease treatment |
| US20190184206A1 (en) * | 2016-10-16 | 2019-06-20 | Vibrato Medical, Inc. | Extracorporeal therapeutic ultrasound for promoting angiogenesis |
| WO2018181991A1 (en) * | 2017-03-30 | 2018-10-04 | 国立大学法人東北大学 | Device for treating dementia, method for operating said device, and program |
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