Getting ahead of Alzheimer’s disease: early intervention with focused ultrasound

The amyloid-β (Aβ) hypothesis implicates Aβ protein accumulation in Alzheimer’s disease (AD) onset and progression. However, therapies targeting Aβ have proven insufficient in achieving disease reversal, prompting a shift to focus on early intervention and alternative therapeutic targets. Focused ultrasound (FUS) paired with systemically-introduced microbubbles (μB) is a non-invasive technique for targeted and transient blood–brain barrier opening (BBBO), which has demonstrated Aβ and tau reduction, as well as memory improvement in models of late-stage AD. However, similar to drug treatments for AD, this approach is not sufficient for complete reversal of advanced, symptomatic AD. Here we aim to determine whether early intervention with FUS-BBBO in asymptomatic AD could delay disease onset. Thus, the objective of this study is to measure the protective effects of FUS-BBBO on anxiety, memory and AD-associated protein levels in female and male triple transgenic (3xTg) AD mice treated at an early age and disease state. Here we show that early, repeated intervention with FUS-BBBO decreased anxiety-associated behaviors in the open field test by 463.02 and 37.42% in male and female cohorts, respectively. FUS-BBBO preserved female aptitude for learning in the active place avoidance paradigm, reducing the shock quadrant time by 30.03 and 31.01% in the final long-term and reversal learning trials, respectively. Finally, FUS-BBBO reduced hippocampal accumulation of Aβ40, Aβ42, and total tau in females by 12.54, 13.05, and 3.57%, respectively, and reduced total tau in males by 18.98%. This demonstration of both cognitive and pathological protection could offer a solution for carriers of AD-associated mutations as a safe, non-invasive technique to delay the onset of the cognitive and pathological effects of AD

Texture-Driven Coronary Artery Plaque Characterization Using Wavelet Packet Signatures

High-frequency ultrasound transducers are being widely used to generate high resolution, real time, cross-sectional images of the coronary arteries. In this paper, we present a robust unsupervised texture-derived technique based on multi-channel wavelet frames to delineate atherosclerotic plaque compositions. The intravascular ultrasound (IVUS) signals were acquired from coronary arteries dissected from 32 diseased cadaver hearts employing 40 MHz mechanically rotating, single-element transducers. The wavelet packet representations were classified using a K- means clustering algorithm to generate IVUS-histology color maps (IV-HCMs) and categorize tissues in lipidic, fibrotic and calcified. Finally, two independent observers evaluated the results contrasting the histology images corresponding to the IV-HCMs. Our results show that the proposed algorithm may have great potential as an alternative to existing spectrum-based classification techniques

In Vivo Feasibility of Real-Time Monitoring of Focused Ultrasound Surgery (FUS) Using Harmonic Motion Imaging (HMI)

Abstract-In this study, the Harmonic Motion Imaging for Focused Ultrasound (HMIFU) technique is applied to monitor changes in mechanical properties of tissues during thermal therapy in a transgenic breast cancer mouse model in vivo. An HMIFU system, composed of a 4.5-MHz focused ultrasound (FUS) and a 3.3-MHz phased-array imaging transducer, was mechanically moved to image and ablate the entire tumor. The FUS transducer was driven by an amplitude-modulated (AM) signal at 15 Hz. The acoustic intensity (I sp ta ) was equal to 1050 W/cm 2 at the focus. A digital low-pass filter was used to filter out the spectrum of the FUS beam and its harmonics prior to displacement estimation. The resulting axial displacement was estimated using 1-D crosscorrelation on the acquired RF signals. Results from two mice with eight lesions formed in each mouse (16 lesions total) showed that the average peak-to-peak displacement amplitude before and after lesion formation was respectively equal to 17.34 ± 1.34 µm and 10.98 ± 1.82 µm (p < 0.001). Cell death was also confirmed by hematoxylin and eosin histology. HMI displacement can be used to monitor the relative tissue stiffness changes in real time during heating so that the treatment procedure can be performed in a timeefficient manner. The HMIFU system may, therefore, constitute a cost-efficient and reliable alternative for real-time monitoring of thermal ablation. Index Terms-Acoustic radiation force, breast cancer, focused ultrasound surgery (FUS), harmonic motion imaging, highintensity focused ultrasound (HIFU), in vivo, monitoring, noninvasive estimation, tissue ablation, ultrasound

Assessment of regional myocardial strain using cardiac elastography: Distinguishing infarcted from non-infarcted myocardium,”

Abstract -Estimation of the regional mechanical properties of the cardiac muscle has been shown to play a crucial role in the detection of cardiovascular disease. Current echocardiography-based cardiac motion estimation techniques, such as Doppler Myocardial Imaging (DMI), are limited due to angle dependence. By contrast, elastography, a method designed and used for the detection of tumors, measures displacement and strain by comparing echoes before and aper (not during) a deformation and thus is not angle-dependent. Therefore, the feasibility of cardiac elastography to provide reliable and reproducible displacement and strain estimates from multiple sonographic views was recently demonstrated utilizing RF data from a normal human heart in vivo [ 11. In this paper, we demonstrate this technique utilizing 2D B-scan data in a patient with a known myocardial infarction. Envelopedetected sonographic data was used to estimate regional wall motion and deformation. Displacement and strain estimates were obtained in both non-infarcted, normally contracting and infarcted regions. By obtaining cine-loop and M-Mode elastograms from both regions, the ischemic regions could be identified. In conclusion, elastography may be a clinically viable method for detection of abnormalities of regional wall motion throughout the cardiac cycle

A New Brain Drug Delivery Strategy: Focused Ultrasound-Enhanced Intranasal Drug Delivery

Central nervous system (CNS) diseases are difficult to treat because of the blood-brain barrier (BBB), which prevents most drugs from entering into the brain. Intranasal (IN) administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS) in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+IN) for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After IN administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (IV) drug injection is employed, FUS was also applied after IV injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+IN enhanced drug delivery within the targeted region compared with that achieved by IN only. Despite the fact that the IN route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+IN was not significantly different from that of FUS+IV. As a new drug delivery platform, the FUS+IN technique is potentially useful for treating CNS diseases

Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)- enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain