Investigating the efficacy of a combination Aß-targeted treatment in a mouse model of Alzheimer's disease.

Amyloid-beta peptide (Aß) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Here, we explored the use of a combination treatment to reduce amyloid load through microglial phagocytosis in a mouse model of AD. We hypothesized that using an initial treatment of magnetic resonance image guided focused ultrasound (MRIgFUS) to transiently increase the blood-brain barrier (BBB) permeability and enhance the delivery of an Aß-antibody (BAM-10), followed by scyllo-inositol treatment would result in accelerated clearance. TgCRND8 mice expressing both Swedish (KM670/671NL) and Indiana (V717F) APP mutations under the hamster prion (PrP) promoter at 5 months of age were either treated with scyllo-inositol or received an initial MRIgFUS treatment delivering BAM-10 prior to scyllo-inositol treatment for one month. Treated animals and untreated TgCRND8 littermates were then sacrificed at 6 months of age, and their brains were processed for immunohistochemistry and immunofluorescence. Amyloid load was quantified and analyzed through immunohistochemical staining. Astrocyte and microglial activation were quantified and analyzed through immunofluorescent staining. We found that both the scyllo-inositol treatment and combination treatment, MRIgFUS/BAM10+scyllo-inositol, significantly reduced amyloid load and astrocyte activation in the hippocampus and the cortex. Furthermore, in both treatment paradigms microglial activation and phagocytosis was increased in comparison to the untreated mice. There were no differences detected between the two treatment paradigms. We propose that the 30-day scyllo-inositol treatment saturated the early benefit of the MRIgFUS/BAM-10 treatment. In the future, multiple FUS treatments combined with BAM-10 throughout the duration of scyllo-inositol treatment may lead to more effective amyloid clearance.

Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions.

Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes.

MR-Guided Delivery of Hydrophilic Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound.

PURPOSE: A wide variety of hydrophilic imaging and therapeutic agents are unable to gain access to the central nervous system (CNS) due to the blood-brain barrier (BBB). In particular, unless a particular transporter exists that may transport the agent across the BBB, most agents that are larger than 500 Da or that are hydrophilic will be excluded by the BBB. Glutamate carboxypeptidase II (GCPII), also known as the prostate-specific membrane antigen (PSMA) in the periphery, has been implicated in various neuropsychiatric conditions. As all agents that target GCPII are hydrophilic and thereby excluded from the CNS, we used GCPII as a platform for demonstrating our MR-guided focused ultrasound (MRgFUS) technique for delivery of GCPII/PSMA-specific imaging agents to the brain. PROCEDURES: Female rats underwent MRgFUS-mediated opening of the BBB. After opening of the BBB, either a radio- or fluorescently labeled ureido-based ligand for GCPII/PSMA was administered intravenously. Brain uptake was assessed for 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([18F]DCFPyL) and YC-27, two compounds known to bind GCPII/PSMA with high affinity, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, respectively. Specificity of ligand binding to GCPII/PSMA in the brain was determined with co-administration of a molar excess of ZJ-43, a compound of the same chemical class but different structure from either [18F]DCFPyL or YC-27, which competes for GCPII/PSMA binding. RESULTS: Dynamic PET imaging using [18F]DCFPyL demonstrated that target uptake reached a plateau by ∼1 h after radiotracer administration, with target/background ratios continuing to increase throughout the course of imaging, from a ratio of ∼4:1 at 45 min to ∼7:1 by 80 min. NIRF imaging likewise demonstrated delivery of YC-27 to the brain, with clear visualization of tracer in the brain at 24 h. Tissue uptake of both ligands was greatly diminished by ZJ-43 co-administration, establishing specificity of binding of each to GCPII/PSMA. On gross and histological examination, animals showed no evidence for hemorrhage or other deleterious consequences of MRgFUS. CONCLUSIONS: MRgFUS provided safe opening of the BBB to enable specific delivery of two hydrophilic agents to target tissues within the brain. This platform might facilitate imaging and therapy using a variety of agents that have heretofore been excluded from the CNS.

Preclinical MRI-Guided Focused Ultrasound: A Review of Systems and Current Practices.

Effective preclinical research is a vital component in the development of MRI-guided focused ultrasound (MRgFUS) and its translation to clinic. In this review, we seek to outline the challenges at hand for effective preclinical research, survey different solutions, and underline best practices. Furthermore, we summarize efforts to build and characterize dedicated preclinical MRgFUS equipment, including lab prototypes and available commercial products. Finally, we discuss constraints and considerations specific to using clinical MRgFUS equipment in preclinical research. Specifically, we examine additional hardware that has been used to adapt clinical MRgFUS equipment to better position, constrain, and image preclinical subjects, as well as software solutions that have been used to extend the potential and capabilities of clinical devices.

A novel, flat, electronically-steered phased array transducer for tissue ablation: preliminary results.

Flat, λ/2-spaced phased arrays for therapeutic ultrasound were examined in silico and in vitro. All arrays were made by combining modules made of 64 square elements with 1.5 mm inter-element spacing along both major axes. The arrays were designed to accommodate integrated, co-aligned diagnostic transducers for targeting and monitoring. Six arrays of 1024 elements (16 modules) and four arrays of 6144 elements (96 modules) were modelled and compared according to metrics such as peak pressure amplitude, focal size, ability to be electronically-steered far off-axis and grating lobe amplitude. Two 1024 element prototypes were built and measured in vitro, producing over 100 W of acoustic power. In both cases, the simulation model of the pressure amplitude field was in good agreement with values measured by hydrophone. Using one of the arrays, it was shown that the peak pressure amplitude dropped by only 24% and 25% of the on-axis peak pressure amplitude when steered to the edge of the array (40 mm) at depths of 30 mm and 50 mm. For the 6144 element arrays studied in in silico only, similarly high steerability was found: even when steered 100 mm off-axis, the pressure amplitude decrease at the focus was less than 20%, while the maximum pressure grating lobe was only 20%. Thermal simulations indicate that the modules produce more than enough acoustic power to perform rapid ablations at physiologically relevant depths and steering angles. Arrays such as proposed and tested in this study have enormous potential: their high electronic steerability suggests that they will be able to perform ablations of large volumes without the need for any mechanical translation.