CN121174992A - Controlling the ultrasound program by monitoring microbubble response - Google Patents

Abstract

An ultrasound transducer sonicates a target volume by transmitting a sequence of acoustic pulses to the target volume to change a tissue property, while at least one acoustic detector detects an ultrasound reflected signal from the target volume after each acoustic pulse, and a controller (i) estimates an activity of a contrast agent at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and (ii) controls the ultrasound transducer to change the tissue property based on the estimated activity.

Description

Controlling ultrasound procedures by monitoring microbubble response

Technical Field

The present disclosure relates to systems and methods for monitoring contrast agent response and controlling focused ultrasound therapy.

Background

Non-invasive treatment of lesions affecting the central nervous system using a combination of Focused Ultrasound (FUS) and microbubbles has shown great therapeutic promise. One application involves disruption of the Blood Brain Barrier (BBB), which may allow drug delivery into the brain parenchyma that would otherwise be blocked by the BBB.

In order to reversibly open the BBB, FUS needs to be applied with sufficient strength to render the tissue permeable to the therapeutic agent. However, if the FUS strength is too high, there is a risk of damaging other tissues and/or making the permeability somewhat permanent.

Disclosure of Invention

Thus, careful control of FUS intensity is critical in order to use FUS for BBB opening and to achieve effective drug delivery without damage. To ensure effective treatment and minimize collateral damage, such control should provide real-time feedback in response to both the degree of BBB opening and the risk of tissue damage.

In one aspect, a system for controllably altering tissue properties in the presence of a suspension of a contrast agent is described. The system includes an ultrasound transducer for sonicating a target volume to change a tissue property, the ultrasound transducer emitting a sequence of acoustic pulses toward the target volume, at least one acoustic detector for detecting an ultrasound reflected signal from the target volume after each acoustic pulse, and a controller configured to (i) estimate an activity of a contrast agent at the target volume based on a comparison between values of signal parameters in the reflected signals after successive acoustic pulses, and (ii) control the ultrasound transducer based on the estimated activity to change the tissue property.

In another aspect, a method for controllably altering a tissue property in a target volume in the presence of a contrast agent is described. The method includes the steps of applying a sequence of acoustic pulses to a target volume, detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating an activity of a contrast agent at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling the application of the acoustic pulses to change tissue properties based on the estimated activity.

In another aspect, a system for monitoring cavitation in an internal tissue region in response to applied acoustic energy is described. The system includes an ultrasound transducer including a plurality of spatially distributed elements each for transmitting a sequence of acoustic pulses toward a target volume and causing cavitation of a suspension of contrast agent therein, a plurality of spatially distributed acoustic detectors for detecting ultrasound reflected signals from the target volume after each acoustic pulse, and a controller configured to receive data from the acoustic detectors that characterizes the detected reflected signals and to estimate cavitation levels at least at a plurality of voxel locations spatially spanning the target volume based on at least (i) the received data, (ii) a location of the acoustic detectors, and (iii) a speed of sound between the acoustic detectors and the target volume.

In another aspect, the invention features a method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by sites of aberrant production, aggregation and/or deposition of proteins or other biomolecules in the brain, and wherein a therapeutic and/or contrast agent composition is to be, is being or has been administered to the subject. The method includes applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating an activity of a contrast agent at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling application of the acoustic pulses to alter tissue properties based on the estimated activity without producing clinically significant effects on non-target tissue, thereby increasing delivery of a therapeutic agent to a delivery level of the site.

Drawings

In the drawings, like reference numerals generally refer to like parts throughout the different views. Moreover, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the disclosure. In the following description, various embodiments of the disclosure are described with reference to the following drawings, in which:

fig. 1A schematically depicts an exemplary ultrasound system according to various embodiments of the present disclosure.

Fig. 1B schematically depicts an exemplary MRI system according to various embodiments of the present disclosure.

Fig. 2 depicts an implementation of an acoustic reflector substantially near a target region according to some embodiments.

Fig. 3 is a graph depicting observed and actual concentrations of contrast agent during a focused ultrasound procedure, according to some embodiments.

Fig. 4-9 are graphs depicting indications of cavitation during a focused ultrasound procedure including multiple sonications, according to some embodiments.

FIG. 10 depicts a subtraction image reflecting microbubble cavitation, according to some embodiments.

Fig. 11 is a flow chart illustrating an exemplary method of controllably altering a property of tissue in a target volume in the presence of a contrast agent.

Detailed Description

Fig. 1A illustrates an exemplary ultrasound system 100 for generating and delivering a focused beam of acoustic energy to a target region 101 within a patient. The illustrated system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 driving the phased array 102, a controller 108 in communication with the beamformer 106, and a frequency generator 110 providing input electronic signals to the beamformer 106.

The array 102 may have a curved shape (e.g., spherical or parabolic) or other contoured shape suitable for placement on a patient's body surface, or may include one or more planar or otherwise shaped sections. The dimensions of which may vary between a few millimeters and a few tens of centimeters. The transducer elements 104 of the array 102 may be piezo-ceramic elements and may be mounted in silicone rubber or any other material suitable for attenuating mechanical coupling between the elements 104. Piezoelectric composites may also be used, or generally any material capable of converting electrical energy into acoustic energy. To ensure maximum power transfer to the transducer element 104, the element 104 may be configured for electrical resonance at 50Ω to match the input connector impedance.

The transducer array 102 is coupled to a beamformer 106 that drives individual transducer elements 104 such that they collectively produce a focused ultrasound beam or field. For n transducer elements, the beamformer 106 may include n driver circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120, each driving one of the transducer elements 104. The beamformer 106 receives a Radio Frequency (RF) input signal, typically in the range of 0.1 MHz to 10 MHz, from a frequency generator 110, which may be, for example, a DS345 type generator available from the stanford research systems company. The input signal may be split into n channels for n amplifiers 118 and delay circuits 120 of the beamformer 106. In some embodiments, the frequency generator 110 is integrated with the beamformer 106. The radio frequency generator 110 and the beamformer 106 are configured to drive individual transducer elements 104 of the transducer array 102 at the same frequency but with different phases and/or different amplitudes.

The amplification or attenuation factors α ₁ - αn and phase shifts a ₁ -an applied by the beamformer 106 are used to transmit and focus ultrasonic energy onto the target region 101 through the intervening tissue between the transducer element 104 and the target region and account for wave distortion induced in the intervening tissue. The amplification factor and phase shift are calculated using a controller 108, which may provide the computational function through software, hardware, firmware, hard-wiring, or any combination thereof. In various embodiments, the controller 108 utilizes a general or special purpose digital data processor programmed in a conventional manner with software, and without undue experimentation, determines the frequency, phase shift, and/or magnification factor required to obtain the desired focus or any other desired spatial field pattern at the target region 101. In certain embodiments, the calculation is based on detailed information about the characteristics of the intervening tissue (e.g., type, size, location, properties, structure, thickness, density, structure, etc.) between the transducer element 104 and the target and its effect on acoustic energy propagation. Such information may be obtained from the imager 112. The imager 112 may be, for example, a Magnetic Resonance Imaging (MRI) device, a Computed Tomography (CT) device, a Positron Emission Tomography (PET) device, a Single Photon Emission Computed Tomography (SPECT) device, or an ultrasound examination device. The image acquisition may be three-dimensional (3D), or alternatively, the imager 112 may provide a set of two-dimensional (2D) images suitable for reconstructing a three-dimensional image of the target region 101 and/or other region (e.g., the region surrounding the target 101 or another target region). The image processing functions may be implemented in the imager 112, the controller 108, or a separate device. In addition, as described further below, the ultrasound system 100 and/or the imager 112 may be used to detect signals from an acoustic reflector (e.g., microbubbles 202, see fig. 2) that is located substantially near the target region 101. Additionally or alternatively, the system 100 may include an acoustic signal detection device (such as a hydrophone or suitable alternative) 124 that detects transmitted or reflected ultrasound from the acoustic reflector and may provide its received signal to the controller 108 for further processing. Furthermore, the ultrasound system 100 may include an administration system 126 for introducing the acoustic reflector parenterally into the patient's body. The imager 112, acoustic signal detection device 124 and/or application system 126 may operate using the same controller 108 that facilitates transducer operation, alternatively they may be separately controlled by one or more separate controllers that are in communication with each other.

Fig. 1B shows an exemplary imager, namely MRI device 112. The device 112 may include a cylindrical electromagnet 134 that generates the necessary static magnetic field within an aperture 136 of the electromagnet 134. During a medical procedure, a patient is placed inside the aperture 136 on the movable support 138. A region of interest 140 within the patient (e.g., the patient's head) may be positioned within an imaging region 142, wherein the electromagnets 134 generate a substantially uniform field. A set of cylindrical magnetic field gradient coils 144 may also be disposed within the bore 136 and around the patient. The gradient coils 144 generate magnetic field gradients of a predetermined magnitude at predetermined times and in three mutually orthogonal directions. With field gradients, different spatial locations may be associated with different precession frequencies, thereby imparting spatial resolution to a Magnetic Resonance (MR) image. An RF transmitter coil 146 surrounding the imaging region 142 transmits RF pulses into the imaging region 142 to cause tissue of the patient to transmit MR response signals. The raw MR response signals are sensed by the RF coils 146 and passed to the MR controller 148, which then calculates an MR image that can be displayed to the user. Alternatively, separate MR transmitter and receiver coils may also be used. Images acquired using MRI device 112 may provide radiologists and physicians with visual contrast between different tissues, and internal detailed views of patient anatomy that cannot be visualized using conventional X-ray techniques.

The MRI controller 148 may control the pulse sequence, i.e., the magnetic field gradient and RF excitation pulses, and the relative timing and intensity of the response detection periods. The MR response signals are amplified, conditioned, and digitized into raw data using conventional image processing systems and further converted into an array of image data by methods known to those of ordinary skill in the art. Based on the image data, a target region (e.g., a tumor or target BBB) can be identified.

For targeted drug delivery or tumor ablation, the location of the target region 101 needs to be determined with high accuracy. Thus, in various embodiments, the imager 112 is first activated to acquire an image of the target region 101 and/or non-target region (e.g., healthy tissue surrounding the target region, intermediate tissue between the transducer array 102 and the target region 101, and/or any region located near the target), and determine anatomical characteristics (e.g., tissue type, location, size, thickness, density, structure, shape, vascularization) associated therewith based thereon. For example, the tissue volume may be represented as a set of 3D voxels based on a 3D image or a series of 2D image slices, and may include a target region 101 and/or a non-target region.

In order to produce high quality focusing at the target region 101, it may be necessary to calibrate the transducer element 104 and account for transducer geometry imperfections caused by, for example, movement, displacement and/or deformation of the transducer element 104 from its intended position. Furthermore, these wave distortions may also need to be taken into account in order to improve the focusing properties at the target region 101, since ultrasound waves may be scattered, absorbed, reflected and/or refracted as they travel through non-uniform intermediate tissue located between the transducer element 104 and the target region 101.

Referring to fig. 2, ultrasonic waves emitted from all (or at least some) of the transducer elements 104 are reflected by an acoustic reflector 202. The acoustic reflector 202 may consist essentially of microbubbles that are generated by ultrasound and/or introduced parenterally by an administration system. In some embodiments, the application system 126 introduces seed microbubbles into the target region 101, and then activates the transducer 102 to emit ultrasound waves to the seed microbubbles for use in generating a cloud of microbubbles. Methods of generating microbubbles and/or introducing microbubbles into target region 101 are provided, for example, in PCT publication No. WO 2018/020315, PCT application No. PCT/US2018/064058 (submitted on day 5 of 2018, 12), PCT/US 2018/064812 (submitted on day 11 of 2018, 12), PCT/IB2018/000841 (submitted on day 29 of 2018, 6), and PCT/US2018/064066 (submitted on day 5 of 2018, 12), U.S. patent publication No. 2019/0083065, and U.S. patent application No. 15/837,392 (submitted on day 11 of 2017, 12), the contents of which are incorporated herein by reference.

It has been proposed in the past to use reflected signals from an acoustic contrast agent containing microbubbles 202 to assess blood perfusion. Referring to fig. 3, the first acoustic irradiation destroys some of the microbubbles of the contrast agent by cavitation. The intensity of the reflected signal from the second acoustic irradiation depends on the extent of this disruption and the delay between acoustic irradiation during which the concentration of microbubbles is replenished by blood perfusion. By fitting the reflected intensities of the continuous acoustic radiation to the model, the blood perfusion coefficients can be extracted.

In fig. 3, the "observed concentration" curve corresponds to the amplitude of the reflected signal at each acoustic irradiation. The "actual concentration" curve shows how the acoustic irradiation pulse destroys a portion of the microbubbles and how the concentration partially recovers due to cycling, and thus, this destroyed and recovered cycling can be reflected and used to estimate the perfusion rate. When FUS intensity is insufficient to generate microbubble cavitation, a flat (stable) reflected signal from all pulses in the pulse train is obtained.

In accordance with embodiments described herein, reflectance measurements of such pulse sequences may be used to detect the onset of dynamic cavitation of microbubbles and estimate the extent of such cavitation activity. Since cavitation is the basis of BBB destruction, such measurements can be used to monitor and control the extent of BBB destruction. In particular, the detected change in reflected signal from the pulses in the pulse train can be used to identify the onset of microbubble cavitation. Furthermore, this difference can be quantified to infer a quantitative value of the nullification activity, which in turn is related to the probability and extent of BBB destruction.

In various embodiments, the analysis is performed using the first harmonic of the transmitted signal (i.e., using the reflected signal at the same frequency as the transmitted signal). However, it should be understood that any other frequency band of the reflected signal may be used. For the measurement itself, a single hydrophone or an array of hydrophones may be employed. Without loss of generality, the following description assumes that a hydrophone array is used to detect signals. Since the difference between the two reflected signals through the skull is monitored, the effects due to aberrations and attenuation are eliminated and quantitative results are typically obtained without the need for system calibration.

There are several mathematical methods available for analyzing the measurement data. One approach is to compare the reflected signal strengths of two consecutive pulses. If there are more than two pulses in the pulse train, the variance of the intensities in the train can be used as a measure. Statistical analysis methods such as analysis of variance (ANOVA) and mean Analysis (ANOM) can be employed to obtain more quantitative results. These methods can be used for data from a single hydrophone or an array of hydrophones.

There are significant advantages to using ANOVA or ANOM to monitor cavitation when using a hydrophone array. In these methods, the amplitude measurement set of each pulse is compared. Due to the large number of readings, the analysis tends to be more sensitive to changes and quantifies the differences between pulses, thereby quantitatively estimating cavitation levels.

The reflected signal has two components, amplitude and phase. Statistical analysis can be applied to the phase portions as well as the amplitudes, and the differences between the phase gathers can also be used to identify the onset of cavitation. The combination of results using multiple analysis techniques on different components of the measured data may facilitate the statistical confidence level of the resulting results.

Typical pulses in a pulse sequence are 10 to 100 milliseconds long when using an ultrasonic frequency of 100 kHz to 1000 kHz. Different pulse lengths may be used, especially when different FUS frequencies are used. Typical delays between pulses in a pulse train are 0.5 to 5 milliseconds. In order to increase the measurement sensitivity, a shorter delay time (about 1 millisecond) is preferably used.

The use of such short pulses with hydrophone arrays enables the generation of 3D acoustic activity maps of the target region, a procedure also known as passive acoustic mapping or PAM. This may be achieved by constructing a 3D image of the spatial sound field using the reflected signals from the spatially distributed transducer elements 104. The distance between each transducer element and each voxel in the spatial region of interest and the speed of sound through the relevant tissue are known, and thus, based on time of flight, and by summing the measurements from all the transducer elements to account for degeneracy, the response of each voxel to an event can be calculated. Thus, the above described analysis method can be performed voxel by voxel in the target region or volume, providing spatial information related to treatment progress, efficacy and safety.

In particular, generating a cavitation activity map for each pulse in the sequence facilitates a comparison between two pulses (e.g., a first pulse and a second pulse in the sequence), and thus generates a 3D map of effective dynamic cavitation and BBB destruction probabilities. These probability maps can be superimposed on the MRI map to estimate treatment efficacy and coverage.

Another 3D spatial reconstruction method is to reconstruct a single 2D plane within the target and use angular spectroscopy to create neighboring planes and thereby create a 3D spatial map. Angular spectroscopy may involve expanding a complex wave field into the sum of plane waves having the same frequency and different directions. The technique may predict the sound pressure field distribution over a plane based on knowledge of the pressure field distribution at parallel planes.

The following paragraphs present the results of a typical experiment involving 10 sonication cycles, where each cycle is a sequence of 10 sonications. In each successive ultrasound treatment, the drive voltage is increased by 0.05V, which in turn increases the FUS power. Fig. 4 shows the average signal from all the hydrophones in the array as a function of individual acoustic irradiance, with 1024 hydrophones in the array. The driving voltage and the number of sonications are also indicated. As FUS power increases, the total reflected signal also increases. The figure shows that dynamic cavitation starts with sonication 5 (S5). This is better illustrated in fig. 5, where the data has been normalized to the maximum value of each sonication. Referring back to fig. 4, starting from sonication 5 (S5), the response decreases with sonication. It is assumed that after each pulse, a portion of the microbubbles are destroyed by the sonication in the sonicated region and thus the response at the next pulse is lower. The fit to the average response level per pulse showing a decrease in response may be an indication of qualitative and quantitative cavitation. In other words, in addition to the quantitative characteristics that can be derived from the drop in response, the drop itself can also provide the qualitative impression of cavitation indicated. As can be seen from fig. 4, the change in response is not disordered but continuously decays. Thus, the controller or observer can qualitatively determine when cavitation is first indicated by means of the decay itself (specifically during S5 in fig. 4).

Applying ANOVA to the normalized data allows the onset of dynamic cavitation to be detected earlier. Fig. 6 shows the Fisher ratio (F) and the probability that the new dataset is equivalent to the previous dataset. The evaluation was performed sequentially after each sonication cycle. The upper and lower dashed lines represent confidence levels of 95% and 99%, respectively. Dynamic cavitation was detected in sonication 4 (S4) with a confidence of 99%.

Fig. 7 shows the result of ANOM applied to the same dataset. In this case, the mean of the data for each sonication was compared to a 95% Lower Decision Line (LDL). Once the result crosses the zero line, the data set may be declared inequality with the previous data set with a 95% confidence level. In the case shown, the sensitivity of the method is not as good as that of ANOVA.

To obtain quantitative information about dynamic cavitation activity and estimate the probability of BBB destruction, the difference between the number of repetitions within the sonication sequence can be preferably assessed (fig. 8). ANOVA exhibits a lower sensitivity to cavitation onset of the dataset (fig. 9), so normalized mean and amplitude differences of cavitation detection are preferably used to quantify the cavitation activity detected.

The calculated cavitation level may be used in a control loop by which to gradually increase the FUS power until cavitation is first detected, and then until the difference in average amplitude between successive pulses reaches a level indicative of a cavitation level corresponding to the desired level of BBB opening (or a high probability that the BBB will open to the desired level). In some cases, there is no upper limit on the ideal degree of BBB opening, and FUS power can be increased until cavitation levels reach levels at risk of tissue damage, at which point opening or power reduction can be stopped. In other cases, a specific amount of BBB opening is required, e.g., an amount corresponding to an effective porosity that substantially matches the molecular size of the therapeutic agent. By avoiding excessive opening of the BBB, target molecules that have passed the BBB can be captured to some extent behind it when sonication is stopped and the BBB begins to re-close.

The combination of a short pulse and a plurality of distributed acoustic sensors also enables a simple 3D reconstruction of the acoustic activity after each pulse. This can be achieved by constructing a 3D image of the spatial sound field using the reflected signals from the spatially distributed transducer elements. The distance between each transducer element and each voxel in the spatial region of interest and the speed of sound through the relevant tissue are known, and thus, based on time of flight, and by summing the measurements from all the transducer elements to account for degeneracy, the response of each voxel to an event can be calculated. Thus, the above described analysis method can be performed voxel by voxel in the target region or volume, providing spatial information related to treatment progress, efficacy and safety.

Figure 10 shows a subtraction image (axis dimension in millimeters) reflecting microbubble cavitation. When the acoustic irradiation power reaches the cavitation threshold, an acoustic activity slightly off the target (0, 0) is observed (fig. 10a and 10 b). As the power increases (fig. 10c and 10 d), the cavitation level increases, as does the volume in which this activity occurs. Once calibrated, the measurements can be used to express the probability of BBB destruction in a specific region of the target volume.

Embodiments of the invention may increase permeability of the BBB to allow passage of biological agents such as antibodies and therapeutic agents (e.g., busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan/SN-38, carboplatin, doxorubicin, vinca, vincristine, procarbazine, paclitaxel, fotemustine, ifosfamide/4-hydroxyifosfamide/aldicapnide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel or cytarabine (cytarabine, ara-C)/ara-U) for the treatment of tumors (such as GMB), for the treatment of neurodegenerative diseases (e.g., anti-beta amyloid antibodies Aducanumab and anti-antibodies) and for the treatment of Central Nervous System (CNS) infections.

A representative hardware platform for practicing the present invention is described in U.S. patent publication 2020/0139558, the entire disclosure of which is hereby incorporated by reference. The hardware system may include an imaging device (e.g., a Magnetic Resonance Imaging (MRI) device) for characterizing tissue types and/or properties of the target BBB region and/or tissue surrounding it, each tissue type and location, depending on its properties, may have a corresponding cavitation tolerance, and thus the imaging device may be used to spatially characterize tissue tolerance and the spatial representation may be used for comparison with cavitation effect spatial maps generated and updated as described above. The' 9158 application also describes suitable ultrasound transducer devices and driver circuitry.

More generally, the functions for targeted BBB region disruption in a controlled and reversible manner can be built into one or more modules implemented in hardware, software, or a combination of both. For embodiments in which functionality is provided as one or more software programs, the programs may be written in any of several high-level languages, such as PYTHON, FORTRAN, PASCAL, JAVA, C, C ++, c#, BASIC, various scripting languages, and/or HTML. In addition, the software may be implemented in assembly language for a microprocessor built into the target computer, e.g., if the software is configured to run on an IBM PC or PC cloning machine, it may be implemented in Intel 80x86 assembly language. The software may be embodied on an article of manufacture including, but not limited to, a floppy disk, a flash disk, a hard disk, an optical disk, a magnetic tape, PROM, EPROM, EEPROM, a field programmable gate array, or a CD-ROM. Embodiments using hardware circuitry may be implemented using, for example, one or more FPGA, CPLD, or ASIC processors.

As used herein, the term "substantially" refers to ±10% of the tissue volume, in some embodiments, ±5% of the tissue volume. By "clinically significant" is meant that the clinician considers the adverse (sometimes less than ideal) effects on the tissue to be significant, e.g., causing unreasonable damage in a particular treatment.

In one aspect, the invention relates to a method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by a site of aberrant production, aggregation and/or deposition of proteins or other biomolecules in the brain, and wherein a therapeutic agent and/or microbubble composition is to be, is being or has been administered to the subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling the application of the acoustic pulses to alter tissue properties without clinically significant effects on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents.

In various embodiments, the neurological disease or disorder is selected from the group consisting of Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's Disease (HD), amyotrophic Lateral Sclerosis (ALS), dementia with lewy bodies, spinocerebellar ataxia, and amyotrophic lateral sclerosis, frontotemporal disease, multiple system atrophy, four-fold tauopathies, and prion diseases. In some embodiments, the site is selected from the group consisting of senile plaques, neurofibrillary tangles, neuronal inclusion bodies, lewy bodies, glial inclusion bodies, cytoplasmic inclusion bodies, and polyglutamine aggregates. In some embodiments, the protein exhibiting aberrant production, aggregation and/or deposition is selected from the group consisting of beta amyloid (aβ), tau protein, TDP-43, alpha-synuclein, FUS/TLS, SOD1 and huntingtin.

In various embodiments, the therapeutic agent comprises a small molecule or a biologic drug. In some embodiments, the therapeutic agent is or includes a biologic drug. In some embodiments, the therapeutic agent is selected from the group consisting of a gene therapy agent, a vaccine, an antisense oligonucleotide (ASO), a protein therapeutic agent, a modified mRNA agent, and an RNAi agent.

In some embodiments, the therapeutic agent is or includes an antibody, an antibody-like molecule, or an antigen-binding fragment thereof. In some embodiments, the therapeutic agent specifically binds to a protein or other biological molecule that exhibits aberrant production, aggregation and/or deposition. In some embodiments, the therapeutic agent is selected from a non-specific clearance antibody (e.g., intravenous immunoglobulin, also known as IVIg), an anti-beta amyloid antibody (e.g., aducanumab, gantenerumab, lecanemab and donanemab), an anti-tau antibody (e.g., semorinemab, gosuranemab, tilavonemab and zagotenemab), an anti-TREM 2 antibody (e.g., AL 002), an anti-alpha synuclein antibody (e.g., cinpanemab, prasinezumab, lu AF82422, ABBV-0805, and MEDI 1341), and/or a combination thereof.

In some embodiments, the therapeutic agent is or includes a small molecule drug. In some embodiments, the therapeutic agent provides one or more of synaptic plasticity, neuroprotection, reduction of inflammation, regulation of neurotransmitter receptors, reduction of oxidative stress. In some embodiments, the therapeutic agent is selected from the group consisting of donepezil, galantamine, rivastigmine, memantine, suvorexant, carbidopa-levodopa, selegiline, rasagiline, sand fenamide, entacapone, benzatropine, tolcapone, epicapone, p Mo Fanse lin (nuplazid), itratheophylline, and amantadine, and combinations thereof.

In some embodiments, the therapeutic agent is formulated in liposomes. In some embodiments, the therapeutic agent is delivered via a viral vector.

Fig. 1 is a flowchart showing an example process 400 for controllably causing tissue destruction in an anatomical region within a target, according to some embodiments. The process may be controlled by instructions stored in a computer memory or non-transitory computer readable storage medium. These instructions may be included in one or more programs stored on a non-transitory computer readable storage medium. The instructions, when executed by one or more processors (e.g., 108 and/or 148), cause the system to perform the process. The non-transitory computer readable storage medium may include one or more solid state storage devices (e.g., flash memory), magnetic or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that may be interpreted by one or more processors. Some operations in the process may be combined and the order of some operations may be changed.

Fig. 11 is a flowchart showing an example process 1100 for controllably altering tissue properties in the presence of a suspension of a contrast agent, according to some embodiments. The process may be controlled by instructions stored in a computer memory or non-transitory computer readable storage medium. These instructions may be included in one or more programs stored on a non-transitory computer readable storage medium. The instructions, when executed by one or more processors (e.g., 108 and/or 148), cause the system to perform the process. The non-transitory computer readable storage medium may include one or more solid state storage devices (e.g., flash memory), magnetic or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that may be interpreted by one or more processors. Some operations in the process may be combined and the order of some operations may be changed.

In operation 1102, an ultrasound transducer (e.g., 102) transmits a sequence of acoustic pulses to a target volume.

In operation 1104, at least one acoustic detector (e.g., element 104 or hydrophone) detects ultrasound reflected signals from the target volume after each acoustic pulse.

In operation 1106, the controller (e.g., 108 and/or 148) computationally estimates an activity of the contrast agent at the target volume based on a comparison between values of signal parameters in the reflected signal after the continuous acoustic pulse.

In operation 1108, the controller controls the ultrasound transducer based on the estimated activity to change the tissue property. In some embodiments, the controller controls the ultrasound transducer based on the estimated activity to alter the tissue property without clinically significant impact on non-target tissue.

In some embodiments, the modification to the tissue property includes disrupting a tissue barrier to increase permeability of the barrier, neuromodulating tissue neurons, activating an sonodynamic drug, activating a contrast agent carrier for drug and/or gene delivery, thrombolysis, and/or inducing an ischemic effect.

In some embodiments, the change to the tissue property is to disrupt the tissue barrier to increase permeability of the barrier, wherein the tissue barrier is a blood brain barrier, a blood retina barrier, skin, mucous membrane, cell membrane, or nuclear membrane, and the permeability is increased sufficiently to allow passage of a therapeutic agent therethrough, wherein the therapeutic agent is selected for treatment of a tumor, a neurodegenerative disease, an enzyme deficiency, or a CNS infection.

In some embodiments, the comparison is based on a variance, a mean to variance, or a ratio of mean to standard deviation, of the signal amplitudes measured by the plurality of acoustic detectors, a full spectrum of the reflected signal, a first harmonic of the reflected signal, or an indication that the signal amplitudes measured by the plurality of acoustic detectors are decreasing.

In some embodiments, the contrast agent comprises gas-filled bubbles or phase-shifted droplets having a size in the range of 150nm to 20 μm and the activity of the contrast agent is the onset of cavitation, and/or the extent of cavitation, wherein the extent of cavitation is estimated based on the difference between the average measured amplitudes of successive pulses.

In some embodiments, the spacing between consecutive acoustic pulses is no greater than 3 ms, the signal parameter is phase or amplitude, and the comparison between the values of the signal parameter in the reflected signal coincides with the first harmonic of the emission spectrum of the consecutive acoustic pulses.

Treatment example

In some aspects, the present disclosure provides a method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by abnormal production, aggregation and/or deposition of proteins or other biomolecules in the brain. In some embodiments, the neurological disease or disorder is selected from the group consisting of Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's Disease (HD), amyotrophic Lateral Sclerosis (ALS), dementia with lewy bodies, spinocerebellar ataxia, and amyotrophic lateral sclerosis, frontotemporal disease, multiple system atrophy, four-fold tauopathy, and prion disease.

Alzheimer's disease patients exhibit senile plaques consisting mainly of beta amyloid (Abeta), neurofibrillary tangles containing Tau protein, neuronal inclusion bodies of TDP-43, and Lewis bodies containing alpha-synuclein. Patients with parkinson's disease exhibit a lewy body comprising alpha-synuclein. Patients with amyotrophic lateral sclerosis have neuronal inclusion bodies comprising TAR DNA binding protein 43 (TDP-43), sarcoma fusion/liposarcoma translocation (FUS/TLS) and superoxide dismutase-1 (SOD 1). Huntington's disease is a progressive brain disorder caused by mutation of a gene encoding huntingtin, resulting in progressive damage to brain cells by abnormal muteins. Dementia with lewy bodies is characterized by lewy bodies containing alpha-synuclein, senile plaques consisting mainly of beta amyloid (aβ), and neurofibrillary tangles of Tau protein. Patients with frontotemporal leaf disease will show neuronal and glial inclusion bodies consisting of Tau, TDP-43 and FUS/TLS. Multisystem atrophy is characterized by glial cytoplasmic inclusion bodies of alpha-synuclein. Thus, there appears to be an overlap between proteins associated with these diseases that exhibit aberrant production, aggregation and/or deposition. A single neurodegenerative disease may be associated with multiple proteins (or other biomolecules) that exhibit abnormal production, aggregation and/or deposition. On the other hand, individual proteins exhibiting abnormal production, aggregation and/or deposition may also be associated with various diseases. For example, while aβ plaques and tau tangles are typical features of alzheimer's disease, more than 50 percent of alzheimer's cases found a lewy body typical of parkinson's disease, and more than 40 percent of cases found a neuronal inclusion body consisting of the protein TDP-43. Similarly, in dementia with lewy bodies, i.e. dementia closely related to parkinson's disease with some features of alzheimer's, typical lewis bodies rich in alpha-synuclein are accompanied by aβ plaques in 60 percent of cases and tau tangles in 50 percent of cases. Similarly, four-fold tauopathies (a group of neurodegenerative diseases defined by cytoplasmic inclusion bodies consisting mainly of tau subtypes with four microtubule-binding domains) are associated with at least three clinical manifestations, (1) progressive supranuclear palsy, which is manifested as axial rigidity and eye movement problems unless typical parkinson's disease, and (2) corticobasal degeneration presents with frontal lobe-like dementia, with focal cortical syndromes, including progressive disuse or progressive aphasia, and (3) silvered granulomatosis, an increasingly valued condition of the elderly, affecting the medial temporal lobe, and associated with amnesia cognitive impairment.

Thus, in some aspects, the present disclosure provides a method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by abnormal production, aggregation and/or deposition of proteins or other biomolecules in the brain, wherein a therapeutic agent and/or a microbubble composition is to, is being or has been administered to the subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing clinically significant effects on non-target tissue, thereby increasing delivery of the therapeutic agent to the delivery level of the site as compared to a control. in some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the neurological disease or disorder is alzheimer's disease and the site is selected from the group consisting of senile plaques comprising beta amyloid (aβ), neurofibrillary tangles comprising Tau protein, neuronal inclusion bodies comprising TDP-43, and lewy bodies comprising alpha synuclein. In some embodiments, the neurological disease or disorder is parkinson's disease and the site is a lewy body comprising alpha-synuclein. In some embodiments, the neurological disease or disorder is amyotrophic lateral sclerosis, and the site is a neuronal inclusion body comprising TAR DNA binding protein 43 (TDP-43), sarcoma fusion/liposarcoma translocation (FUS/TLS), and superoxide dismutase-1 (SOD 1). In some embodiments, the neurological disease or disorder is huntington's disease and the site is the neuronal nuclear inclusion body of huntingtin. In some embodiments, the neurological disease or disorder is lewy body dementia, and the sites are lewy bodies comprising alpha-synuclein, senile plaques comprising beta amyloid (aβ), and neurofibrillary tangles comprising Tau protein. In some embodiments, the neurological disease or disorder is frontotemporal lobe disease and the site is a neuron and glial inclusion body composed of Tau, TDP-43 and FUS/TLS. In some embodiments, the neurological disease or disorder is multiple system atrophy and the site is a glial cytoplasmic inclusion body of alpha-synuclein. in some embodiments, the neurological disease or disorder is a four-fold tauopathy, and the site is a cytoplasmic inclusion body consisting essentially of tau isoforms having four microtubule-binding domains.

Diseases associated with the aggregation and/or accumulation of proteins (or other biomolecules) that exhibit abnormal production, aggregation and/or deposition also include prion diseases, i.e., infectious spongiform encephalopathies, such as bovine spongiform encephalopathy (BSE or mad cow disease) and creutzfeldt-jakob disease. These diseases are characterized by senile plaques formed by PrP proteins. Thus, in some aspects, the present disclosure provides a method of treating prion diseases in which a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signals after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery of the therapeutic agent to the delivery level of the site as compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents.

Alzheimer's disease

Alzheimer's Disease (AD) is a complex, progressive debilitating and fatal neurodegenerative disease. As the world population ages, the frequency of AD is rapidly increasing. Currently, the united states estimates 650 tens of thousands of individuals with AD, and by 2050, this number is expected to increase to over 1300 tens of thousands. About 15% of the us population over 60 years of age has prodromal AD, and about 40% has preclinical AD. Similar trends are seen globally, with the expected global population of AD dementia patients exceeding 1 million by 2050, unless means to delay, prevent or treat AD are found. There is a great need for therapeutic approaches to prevent or reverse the underlying pathology of AD.

The cellular and molecular mechanisms of AD are not well understood. Researchers have reported that AD is associated with inheritance, environmental factors, and lifestyle. AD patients have heterogeneity in that they may be in preclinical AD stages as long as twenty years or more without ever exhibiting any clinical symptoms, i.e. Mild Cognitive Impairment (MCI), AD dementia or functional decline. Furthermore, misdiagnosis of AD patients is more common, because 10% to 30% of individuals clinically diagnosed with AD dementia show no AD neurodegenerative lesions at necropsy.

The failure rate for all types of AD therapies exceeds 99% and for Disease Modifying Therapy (DMT) is 100%. Thus, in addition to new methods for developing therapeutic agents, there is a need for methods for targeted delivery of therapeutic agents, such as those disclosed herein.

Alzheimer's disease patients are associated with senile plaques consisting of beta amyloid (Abeta), neurofibrillary tangles containing Tau protein, neuronal inclusion bodies of TDP-43, and Lewis bodies containing alpha-synuclein. As a relatively small peptide of 4 to 4.4 kDa, aβ is the main component of amyloid deposition. Intracellular aβ proteins are widely found in neurons and are associated with inflammatory and antioxidant activity, regulation of cholesterol transport, and activation of kinases. However, aβ is one of the most well known components in the formation of neurodegenerative diseases including AD. Aβ is composed of approximately 36 to 43 amino acids and is derived from an Amyloid Precursor Protein (APP), which is a glycoprotein having 695 to 770 amino acids. APP can be cleaved into fragments by α, β and γ secretases and forms aβ proteins by the action of the β and γ secretases. Aβ proteins contain two important regions that play a major role in the formation of insoluble amyloid fibrils.

Microtubule-associated Tau protein (the name of which is from a "tubulin-associated unit") is highly expressed in the brain. Microtubules are the major protein of the cytoskeleton. The main function of Tau proteins is to stabilize microtubules by binding to microtubules and other proteins. To perform these functions, the Tau protein is phosphorylated at normal levels. Hyperphosphorylation of Tau proteins is thought to result in conformational changes and aggregation of Tau proteins. Other post-translational modifications, such as glycosylation, saccharification, polyamine, and nitration, may also play a role in aggregation. Accordingly, in some aspects, the present disclosure provides a method of treating Alzheimer's Disease (AD), wherein a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating an activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing delivery of a delivery level of the therapeutic agent to the site as compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the protein exhibiting aberrant production, aggregation and/or deposition is selected from the group consisting of beta amyloid peptide (aβ), neurofibrillary tangles and tau proteins. In some embodiments, the therapeutic agent is selected from the group consisting of non-specific clearance antibodies (e.g., intravenous immunoglobulins, also known as IVIg), anti-beta amyloid antibodies (e.g., aducanumab, gantenerumab, lecanemab and donanemab), anti-tau antibodies (e.g., semorinemab, gosuranemab, tilavonemab and zagotenemab), anti-TREM 2 antibodies (e.g., AL 002), donepezil, rivastigmine, memantine, and galantamine, and combinations thereof. In some embodiments, the therapeutic agent is aducanaumab. Some therapeutic agents are disclosed in WO 2014/089500 and WO 2021/108861, and the contents of which are incorporated herein by reference.

Parkinson's disease

Parkinson's Disease (PD) is a long-term degenerative disorder of the central nervous system that can lead to unexpected or uncontrolled movements such as tremors, stiffness, and difficulties in balance and coordination. Symptoms usually start gradually and worsen over time. As the disease progresses, the patient may have difficulty walking and speaking. They may also have psychological and behavioral changes, sleep problems, depression, memory difficulties and fatigue. The occurrence of this disease is characterized by the accumulation of misfolded α -synuclein in the brain. In general, anxiety, tremor, stiffness, depression, bradykinesia, and dysposture are the most common symptoms of parkinson's disease.

The Lewy Body (LB), consisting mainly of α -synuclein, is a neuropathological feature of patients with Parkinson's Disease (PD). However, it is increasingly recognized that PD is often associated with cognitive deficits, and that a significant number of patients eventually develop dementia.

Alpha-synuclein is associated with a variety of neurodegenerative diseases known as "synucleinopathies". The natural unfolded alpha-synuclein (alpha-Syn) is a 14 kDa and highly conserved protein, located in different regions of the brain. Since this protein shows synaptic and nuclear localization, it is preferably named "alpha-synuclein". alpha-Syn modulates dopamine neurotransmission by modulating vesicle dopamine stores. It interacts with tubulin and functions like tau protein. In addition, alpha-Syn shows chaperone activity in the folding of SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins. alpha-Syn plays a vital role in PD, as alpha-Syn is the main fiber component of the lewy body. Overexpression of two mutations in the alpha-Syn gene (a 53T and a 30P) and wild-type alpha-Syn increases misfolding processes and aggregation. In addition, accumulation of abnormal forms of alpha-Syn inhibits proteasome function. In PD brain, ser87 and Ser129 of alpha-Syn were found to be phosphorylated in the aggregates. These serine residues are phosphorylated by casein kinase 1 (CK 1) and casein kinase 2 (CK 2). It is believed that this posttranslational modification has a pathological role in the fibrosis of alpha-Syn.

Accordingly, in some aspects, the present disclosure provides a method of treating Parkinson's Disease (PD), wherein a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signals after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery of the therapeutic agent to the delivery level of the site as compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the protein exhibiting aberrant production, aggregation and/or deposition is an α -synuclein. In some embodiments, the therapeutic agent is selected from the group consisting of anti-alpha-synuclein antibodies (e.g., cinpanemab, prasinezumab, lu AF82422, ABBV-0805, and MEDI 1341), carbidopa-levodopa, selegiline, rasagiline, salfenamide, entacapone, benzatropine, tolcapone, epicapone, p Mo Fanse in (nuplazid), itratheophylline, and amantadine, and combinations thereof.

Multisystem atrophy is characterized by glial cytoplasmic inclusion bodies of alpha-synuclein. Accordingly, in some aspects, the present disclosure provides a method of treating multiple system atrophy in which a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery of a level of delivery of the therapeutic agent to the site as compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the protein exhibiting aberrant production, aggregation and/or deposition is an α -synuclein. In some embodiments, the therapeutic agent is selected from the group consisting of anti-alpha-synuclein antibodies (e.g., cinpanemab, prasinezumab, lu AF82422, ABBV-0805, and MEDI 1341), carbidopa-levodopa, selegiline, rasagiline, salfenamide, entacapone, benzatropine, tolcapone, epicapone, p Mo Fanse in (nuplazid), itratheophylline, and amantadine, and combinations thereof.

Dementia with lewy bodies

Dementia with lewy bodies is characterized by lewy bodies containing alpha-synuclein, senile plaques consisting mainly of beta amyloid (aβ), and neurofibrillary tangles of Tau protein. Dementia with lewy bodies (DLB) is a progressive dementia that results in reduced thinking, reasoning and independent functions. Which may include spontaneous changes in attention and alertness, recurrent hallucinations, rapid Eye Movement (REM) sleep behavior disorders, bradykinesia, tremor, or stiffness. Mutations in genes called SNCA and SNCB can lead to dementia with lewy bodies. Mutation of another gene called GBA or a specific version of the gene called APOE increases the risk of developing this condition, but not directly. Accordingly, in some aspects, the present disclosure provides a method of treating dementia with lewy bodies, wherein a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signals after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery of the therapeutic agent to the delivery level of the site as compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the protein exhibiting aberrant production, aggregation and/or deposition is an α -synuclein. In some embodiments, the therapeutic agent is selected from the group consisting of anti-alpha-synuclein antibodies (e.g., cinpanemab, prasinezumab, lu AF82422, ABBV-0805, and MEDI 1341), rivastigmine, donepezil, galantamine, memantine, carbidopa-levodopa, and combinations thereof. In some embodiments, the methods disclosed herein further comprise detecting a brain-derived biomarker in a plasma sample of the subject. In some embodiments, the method detects a mutation in a gene selected from the group consisting of SNCA, SNCB, and APOE.

Huntington's disease

Huntington's Disease (HD) is a genetic neurodegenerative disorder and the disease is caused by autosomal dominant inheritance. HD patients may exhibit involuntary muscle contractions, motor and psychiatric disorders. The disease inherits in an autosomal dominant fashion and affects the brain and nervous system. Huntingtin undergoes conformational changes with mutation and shows a tendency to aggregate.

In HD, neuropathology is characterized by accumulation of Htt protein aggregates. HD is caused by a large number of CAG repeats in the gene. CAG repeats (polyQ) are considered to be the most important promoters for toxicity of Htt protein aggregates. The polyQ region starts at residue 18 and the number of glutamine residues is the most important marker in HD. Surprisingly, 40 or more CAG repeats always caused neuropathy, while 35 or less CAG repeats never caused neuropathy. However, 27 to 35 CAG repeats may lead to neuropathy during childhood. Accordingly, in some aspects, the present disclosure provides a method of Huntington's Disease (HD) in which a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signals after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing clinically significant effects on non-target tissue, thereby increasing delivery of the therapeutic agent to the delivery level of the site as compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the protein exhibiting aberrant production, aggregation and/or deposition is huntingtin. In some embodiments, the therapeutic agent is selected from an anti-huntingtin antibody and an anti-SEMA 4D antibody (e.g., pemetrexed).

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by degeneration of both the upper motor neurons and the lower motor neurons, resulting in progressive paralysis of limb muscles, speech, swallowing, and respiratory function. Patients with amyotrophic lateral sclerosis have neuronal inclusion bodies comprising TAR DNA binding protein 43 (TDP-43), sarcoma fusion/liposarcoma translocation (FUS/TLS) and superoxide dismutase-1 (SOD 1). ALS pathology is thought to originate at monofocal or multifocal sites and spread in a spatiotemporal fashion through the nerve axis. Insoluble TDP-43 from diseased brain has been reported to induce TDP-43 pathology in neuroblastoma cells overexpressing wtTDP-43, which can be detected by TDP-43 hyperphosphorylation, ubiquitination and aggregation. Accordingly, in some aspects, the present disclosure provides a method of Amyotrophic Lateral Sclerosis (ALS), wherein a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating an activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing delivery of a level of delivery of the therapeutic agent to the site as compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the proteins exhibiting aberrant production, aggregation and/or deposition are TAR DNA binding protein 43 (TDP-43), sarcoma fusion/liposarcoma translocation (FUS/TLS) and superoxide dismutase-1 (SOD 1). In some embodiments, the therapeutic agent is selected from the group consisting of anti-TDP-43 antibodies, anti-SOD 1 antibodies, riluzole, edaravone, sodium phenylbutyrate, and taurine glycol, or a combination thereof.

Spinocerebellar ataxia

Spinocerebellar ataxia (SCAs) is a complex group of neurodegenerative disorders characterized by progressive cerebellar gait and limb ataxia with ocular paralysis, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy and peripheral neuropathy. The onset of disease is usually between the ages of 30 and 50, but it has also been reported to begin early in childhood and in decades after 60 years. Prognosis is different due to the underlying disease of spinocerebellar ataxia subtype. Among SCAs, mutations such AS ATXN1, ATXN2, ATXN3, SCA4, SPTBN2, CACNAIA, ATXN7, KLHL1AS, ATXN10, SCA11, PPP2R2B, KCNC, PRKCG were found. In addition, seven spinocerebellar ataxia subtypes, including SCAs 1, 2, 3/Machado-Joseph disease, 6, 7, 17 and dentate nuclear pallidoluid atrophy (DRPLA), are caused by amplification of CAG repeats in specific genes, resulting in abnormally long polyQ bundles in the encoded protein. Proteins containing amplified polyglutamine fragments appear to exhibit abnormal disposition, leading to the formation and deposition of polyglutamine aggregates in diseased neurons, forming characteristic nuclear or cytoplasmic inclusion bodies, which are neuropathological features of these diseases. Thus, in some aspects, the present disclosure provides a method of treating spinocerebellar properties, wherein a therapeutic agent and/or a microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating an activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signals after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing delivery of a level of delivery of the therapeutic agent to the site as compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the protein exhibiting aberrant production, aggregation and/or deposition is a mutein with amplified polyglutamine bundles. In some embodiments, the therapeutic agent is selected from anti-polyglutamine antibodies.

Frontotemporal disease

Clinical syndromes of frontotemporal dementia have heterogeneity in clinical and neuropathological aspects, but neuroinflammation and the like processes may be common throughout the spectrum of diseases. In recent years, attention has focused on understanding the pathogenic effects of protein misfolding and aggregation, a major feature of post-mortem diagnostic criteria for frontotemporal lobar degeneration (FTLD). These diseases are associated with neuronal and glial inclusions consisting of Tau, TDP-43 and FUS/TLS. Frontotemporal dementia with parkinson's disease-17 (FTDP-17) is a progressive neurodegenerative disease caused by tau gene mutation. In familial FTDP-17, tau gene is mutated and the mutation accelerates formation of neurofibrillary tangles (NFT) in the brain. In addition, the mutation promotes hyperphosphorylation. In some aspects, the present disclosure provides a method of treating frontotemporal dementia, wherein a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery of the level of delivery of the therapeutic agent to the site compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the site is a neuron or glial inclusion body composed of Tau, TDP-43 and FUS/TLS. In some embodiments, the therapeutic agent is an anti-tau antibody.

Tetrad tauopathy

Tetrad (4R-) tauopathies are a group of neurodegenerative diseases defined by cytoplasmic inclusion bodies of tau subtypes. Progressive supranuclear palsy, corticobasal degeneration, silver-philic granulomatosis or glioblastosis are all 4R-tauopathies. Tau is a microtubule-associated protein with versatile functions in the dynamic assembly of the neuronal cytoskeleton, and in these diseases cytoplasmic inclusion bodies consisting mainly of Tau protein subtypes with four microtubule-binding domains were found. Furthermore, the Tau protein is typically located in the axon, but in tauopathies it is located in the dendrite. Thus, the neuronal transport system may disintegrate and microtubules may not function properly. Thus, in some aspects, the present disclosure provides a method of treating a four-repeat (4R-) tauopathy, wherein a therapeutic agent and/or microbubble composition is to be, is being, or has been administered to a subject, the method comprising applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB), detecting a reflected signal from the target volume after each acoustic pulse, computationally estimating the activity of a microbubble at the target volume based on a comparison between values of signal parameters in the reflected signal after successive acoustic pulses, and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing delivery of the therapeutic agent to the delivery level of the site compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse train and/or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the ping sequence and/or the microbubble composition. In any embodiment, the drug delivery level may be measured using imaging techniques including, but not limited to, diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), magnetoencephalography (MEG), and functional near infrared spectroscopy (fNIRS), or a combination thereof, and optionally using tracers, imaging agents, and/or contrast agents. In some embodiments, the protein exhibiting aberrant production, aggregation and/or deposition is a Tau protein. In some embodiments, the therapeutic agent is an anti-tau antibody.

Comments pertaining to the present disclosure

Reference has been made in detail to the various embodiments, examples of which are illustrated in the accompanying drawings. In the above detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention and described embodiments. However, the invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the embodiments.

It will be understood that, although the terms "first," "second," etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another element. For example, a first device may be referred to as a second device, and similarly, a second device may be referred to as a first device, the meaning of the description does not change as long as all occurrences of the first device are renamed consistently and all occurrences of the second device are renamed consistently. The first device and the second device are both devices, but they are not the same device.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the claims. As used in the description of the embodiments and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It is also understood that the term "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. For example, "A, B and/or C" means A only, B only, C only, A and B, A and C, B and C, or A, B and C. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

As used herein, the term "if" may be interpreted to mean "when" or "upon" or in response to "a determination" or "in accordance with" a determination "or" in response to "detecting" that the stated precondition is true, depending on the context. Similarly, the phrase "if a determination (the stated prerequisite is true)" or "when a determination (the stated prerequisite is true)" may be interpreted as meaning that the stated prerequisite is true "once determined" or "in response to a determination" or "upon a determination" or "once detected" or "in response to a detection", depending on the context.

The foregoing description, for purposes of explanation, has been described with reference to specific embodiments. However, the illustrative discussions above are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and its practical application to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated.

Claims (26)

1. A system for controllably altering tissue properties in the presence of a suspension of a contrast agent, the system comprising:

An ultrasound transducer for sonicating a target volume to change tissue properties, the ultrasound transducer emitting a sequence of acoustic pulses to the target volume;

At least one acoustic detector for detecting an ultrasound reflected signal from the target volume after each acoustic pulse, and

A controller configured to (i) estimate an activity of the contrast agent at the target volume based on a comparison between values of signal parameters in reflected signals after successive acoustic pulses, and (ii) control the ultrasound transducer to change the tissue property based on the estimated activity.

2. The system of claim 1, wherein the change to the tissue property comprises:

disrupting the tissue barrier to increase the permeability of the barrier;

performing neuromodulation on tissue neurons;

Activating the sonodynamic therapy drug;

activating the contrast agent carrier for drug and/or gene delivery;

Thrombolysis, and/or

Inducing an ischemic effect.

3. The system of claim 1, wherein:

The alteration to the tissue property is disruption of a tissue barrier to increase permeability of the barrier, wherein the tissue barrier is a blood brain barrier, a blood retina barrier, skin, mucous membrane, cell membrane or nuclear membrane, and

The permeability is increased sufficiently to allow passage therethrough of a therapeutic agent selected for treatment of a tumor, neurodegenerative disease, enzyme deficiency, or CNS infection.

4. The system of claim 1, wherein the comparison is based on:

a variance of signal amplitudes measured by the plurality of acoustic detectors;

The ratio of mean to variance or mean to standard deviation;

A full spectrum of the reflected signal;

The first harmonic of the reflected signal, or

An indication that the signal amplitudes measured by the plurality of acoustic detectors are decreasing.

5. The system of claim 1, wherein:

The contrast agent comprises a gas-filled bubble or phase-shifted droplet having a size in the range of 150 nm to 20 μm, and

The activity of the contrast agent is:

Initiation of cavitation, and/or

The extent of cavitation, wherein the extent of cavitation is estimated based on the difference between the average measured amplitudes of successive pulses.

6. The system of claim 1, wherein:

The interval between successive acoustic pulses is no greater than 3 ms;

the signal parameter being phase or amplitude, and

The comparison between the values of the signal parameters in the reflected signal is consistent with a first harmonic of the emission spectrum of the continuous acoustic pulse.

7. A method of controllably altering a tissue property in a target volume in the presence of a contrast agent, the method comprising the steps of:

applying a sequence of acoustic pulses to the target volume;

detecting a reflected signal from the target volume after each acoustic pulse;

computationally estimating an activity of the contrast agent at the target volume based on a comparison between values of signal parameters in reflected signals after successive acoustic pulses;

the application of the acoustic pulses is controlled based on the estimated activity to alter the tissue property.

8. The method of claim 7, wherein the change to the tissue property is:

disrupting the tissue barrier to increase the permeability of the barrier;

performing neuromodulation on tissue neurons;

Activating the sonodynamic therapy drug;

activating the contrast agent carrier for drug and/or gene delivery;

Thrombolysis, and/or

Inducing an ischemic effect.

9. The method of claim 7, wherein:

The alteration to the tissue property is disruption of a tissue barrier to increase permeability of the barrier, wherein the tissue barrier is a blood brain barrier, a blood retina barrier, skin, mucous membrane, cell membrane or nuclear membrane, and

The permeability is increased sufficiently to allow passage therethrough of a therapeutic agent selected for treatment of a tumor, neurodegenerative disease, enzyme deficiency, or CNS infection.

10. The method of claim 7, wherein the comparing is based on:

a variance of signal amplitudes measured by the plurality of acoustic detectors;

The ratio of mean to variance or mean to standard deviation;

A full spectrum of the reflected signal;

The first harmonic of the reflected signal, or

An indication that the signal amplitudes measured by the plurality of acoustic detectors are decreasing.

11. The method of claim 7, wherein:

The contrast agent comprises a gas-filled bubble or phase-shifted droplet having a size in the range of 150 nm to 20 μm, and

The activity of the contrast agent is:

Initiation of cavitation, and/or

The extent of cavitation, wherein the extent of cavitation is estimated based on the difference between the average measured amplitudes of successive pulses.

12. The method of claim 7, wherein:

The interval between successive acoustic pulses is no greater than 3 ms;

the signal parameter being phase or amplitude, and

The comparison between the values of the signal parameters in the reflected signal is consistent with a first harmonic of the emission spectrum of the continuous acoustic pulse.

13. A system for monitoring cavitation in an internal tissue region responsive to applied acoustic energy, the system comprising:

an ultrasound transducer comprising a plurality of spatially distributed elements each for emitting a sequence of acoustic pulses towards a target volume and causing cavitation of a suspension of contrast agent therein;

a plurality of spatially distributed acoustic detectors for detecting ultrasound reflected signals from the target volume after each acoustic pulse, and

A controller configured to receive data from the acoustic detector that characterizes the detected reflected signal and estimate cavitation levels at least at a plurality of voxel locations spatially spanning the target volume based on at least (i) the received data, (ii) a location of the acoustic detector, and (iii) a speed of sound between the acoustic detector and the target volume.

14. A method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by sites of aberrant production, aggregation and/or deposition of proteins or other biomolecules in the brain, and wherein a therapeutic and/or contrast agent composition is to be, is being or has been administered to the subject, the method comprising:

applying an acoustic pulse sequence to a target volume, wherein the target volume encompasses the site and an adjacent Blood Brain Barrier (BBB);

detecting a reflected signal from the target volume after each acoustic pulse;

Computationally estimating the activity of the contrast agent at the target volume based on a comparison between values of signal parameters in reflected signals after successive acoustic pulses, and

The application of the acoustic pulse is controlled based on the estimated activity to alter tissue properties without producing clinically significant effects on non-target tissue, thereby increasing delivery of the therapeutic agent to the delivery level of the site.

15. The method according to claim 14, wherein:

comparing said level of delivery of said therapeutic agent to a control, and

The controls were:

the level of delivery of the therapeutic agent in a subject that has not received the acoustic pulse sequence and/or the contrast agent composition, or

The level of delivery of the therapeutic agent in the subject being treated prior to administration of the acoustic pulse sequence and/or the contrast agent composition.

16. The method of claim 14, wherein the site is selected from the group consisting of senile plaques, neurofibrillary tangles, neuronal inclusion bodies, lewy bodies, glial inclusion bodies, cytoplasmic inclusion bodies, and polyglutamine aggregates.

17. The method of claim 14, wherein the protein exhibiting aberrant production, aggregation and/or deposition is selected from the group consisting of beta amyloid (aβ), tau protein, TDP-43, alpha synuclein, FUS/TLS, SOD1 and huntingtin.

18. The method of claim 14, wherein the therapeutic agent is or comprises a biologic drug.

19. The method of claim 18, wherein the therapeutic agent is a gene therapy agent, a vaccine, an antisense oligonucleotide (ASO), a protein therapeutic agent, a modified mRNA agent, or an RNAi agent.

20. The method of claim 14, wherein the therapeutic agent is or comprises an antibody, an antibody-like molecule, or an antigen-binding fragment thereof.

21. The method according to claim 20, wherein:

The therapeutic agent specifically binds to proteins or other biomolecules exhibiting abnormal production, aggregation and/or deposition, and

The therapeutic agent is a non-specific clearance antibody, an anti-beta amyloid antibody, an anti-tau antibody, an anti-TREM 2 antibody, and/or an anti-alpha-synuclein antibody.

22. The method of claim 14, wherein the therapeutic agent is or comprises a small molecule drug.

23. The method according to claim 22, wherein:

The therapeutic agent provides synaptic plasticity, neuroprotection, reduction of inflammation, modulation of neurotransmitter receptors and/or reduction of oxidative stress, and

The therapeutic agent is donepezil, galantamine, rivastigmine, memantine, suvorexant, carbidopa-levodopa, selegiline, rasagiline, saphenolide, entacapone, benzatoppine, tolcapone, epicapone, pid Mo Fanse forest (nuplazid), itraconine and/or amantadine.

24. The method of any one of claims 14 to 23, wherein the therapeutic agent is formulated in liposomes or delivered via viral vectors.

25. The method of any one of claims 14 to 23, wherein the neurological disease or disorder is Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's Disease (HD), amyotrophic Lateral Sclerosis (ALS), dementia with lewy bodies, spinocerebellar ataxia, amyotrophic lateral sclerosis, frontotemporal disease, multiple system atrophy, four-fold tauopathy, or prion disease.

26. The method of any one of claims 14 to 23, wherein:

the neurological disease or disorder is a tumor, and the therapeutic agent is selected for treating the tumor;

the nervous system disease or disorder is a central nervous system infection and the therapeutic agent comprises an antibiotic, an antiviral drug, an antiretroviral drug and/or an antifungal drug, or

The neurological disease or disorder is congenital enzyme deficiency disease and the therapeutic agent comprises enzyme replacement therapy.