SAVALNET – Science and Medicine

The blood-brain barrier protects the brain from harmful substances while allowing essential nutrients to pass through. However, it also prevents drugs from reaching the brain. This challenge is especially important in the treatment of Alzheimer’s diseaseA neurodegenerative disorder with limited therapeutic options that places a significant burden on health care due to the aging of the global population.

In the study conducted by Rezai and colleagues, they reported on a proof-of-concept trial involving three patients with Alzheimer’s who were treated with. aducanumabA Amyloid-Binding Monoclonal Antibody With limited penetration across the blood-brain barrier. The experimental treatment involved creating an opening Magnetic resonance imaging (MRI)-guided focused ultrasound To improve drug delivery. they saw a decrease in brain amyloid beta (Aβ) load of targeted areas.

How can focused ultrasound break the barrier?

This generates a mechanical wave, which induces oscillations that transition between compression and rarefaction. The gas bubbles, when injected into the bloodstream and exposed to the ultrasound field, undergo greater compression and expansion than the surrounding tissues and blood. These oscillations produce mechanical tension on the blood vessel walls, causing stretching and opening of the tight junctions between endothelial cells (Figure 1A). Therefore, the integrity of blood brain barrier Compromises are created, allowing the molecules to diffuse into the brain. It is resealed in about 6 hours. This procedure was first performed in animals, followed by preclinical studies and later proved to be safe in people.

Figure 1: Drug administration using focused ultrasound.

What is the role of microbubbles?

These are ultrasound contrast agents commonly used in diagnostic ultrasound to visualize blood flow and vasculature. In this test, a non-pyrogenic suspension of perfluoropropane bubbles (a stable gas that leaves the body through the lungs) encapsulated in phospholipids was administered intravenously during sonication (Figure 1B).

How is the procedure performed?

Focused ultrasound is generated using a hemispheric transducer helmet that surrounds the patient’s head (Figure 1C). It is equipped with 1024 independently controllable ultrasonic sources, driven by a sinusoidal radio frequency voltage. These sources emit magnetic resonance-guided waves, which pass through the skin and scalp and reach the brain.

Variability in the thickness and density of the skull affects the propagation of the waves, causing them to be slightly distorted. This can be fixed by getting data from high resolution computed tomography, which provides information about the shape, thickness, and density of the skull. A computer simulation model calculates the offset offset for each driving signal, restoring sharp focus.

How risky is the intervention?

Opening of the blood-brain barrier requires that the amplitude of the sound wave exceed a threshold, beyond which its permeability increases with pressure amplitude until tissue damage occurs, which leads to erythrocyte extravasation, hemorrhage, apoptosis, and evidenced by necrosis, which is usually associated with collapse of the bubble (called inertial cavitation). Keeping the exposure within safe limits is essential and can be achieved by detecting and interpreting ultrasound signals scattered by microbubbles.

How did you measure the impact?

compared to Positron emission tomography scan with 18F-fluorbetaben To evaluate the difference between the amount of Aβ before and after the treatment series and in the treated area and in the corresponding area of ​​the other hemisphere. However, previous studies have shown that focused ultrasound alone slightly reduced Aβ levels. The reduction observed in the current trial was greater than that seen in previous trials.

What are the estimates?

The trial conducted by Rezaei and colleagues involved only small amounts of tissue from one side of the brain of three patients who were not systematically selected. Extending the treatment to clinically significant amounts on both sides of the brain is important to evaluate its effectiveness. Furthermore, additional studies are needed to establish long-term safety and efficacy, and cost-effective treatment tools should be developed that do not rely on MRI guidance for greater accessibility. This treatment approach, along with agents that remove amyloid beta, may eventually slow the progression of Alzheimer’s disease.