Blood–Brain Barrier Opening in Alzheimer’s Disease Using Mr-Guided Focused Ultrasound

What exactly happens when you are diagnosed with Alzheimer’s?
Alzheimer’s Disease (AD) is the most common neurodegenerative disease. It is a progressive disorder that causes brain cells to waste away (degenerate) and die. Alzheimer's disease is the most common cause of dementia — a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently.

What role does the blood-brain barrier play in all of this and why is it so important?
Alzheimer's disease is characterized by the pathological accumulation of amyloid beta (Aβ) peptides and neurofibrillary tangles containing hyperphosphorylated neuronal tau protein. The blood-brain barrier (BBB), a highly specialized endothelial cell membrane that lines cerebral microvessels, represents the interface between neural cells and circulating cells of the immune system. The BBB is a major obstacle for the effective delivery of therapeutic compounds to the brain, imposing size and biochemical restrictions on the passage of molecules. A safe and effective means of bypassing the barrier temporarily could aid in delivering even large molecules, such as antibodies and growth factors, directly to brain pathology. In simpler words, the medication doctors provide does nott reach the pathological accumulation due to the bbb.

What is this MR-guided focused ultrasound you talk about?
Magnetic resonance guided focused ultrasound (MRgFUS) is a non-invasive way to treat benign and malignant tumors. Ultrasound is a form of energy that can pass through skin, muscle, fat and other soft tissue so no incisions or inserted probes are needed. High intensity focused ultrasound (HIFU) pinpoints a small target and provides a therapeutic effect by raising the temperature high enough to destroy the target with no damage to surrounding tissue. Magnetic resonance imaging (MRI) is used to guide and control the treatment, which is performed while you lie in an MR scanner. Guided by detailed images of your anatomy and the tumor, the physician is able to pinpoint, direct and continuously monitor the treatment.

How has MRgFUS been helpful?
MRgFUS, when coupled with injected microbubbles, transiently opens the BBB with a high degree of spatial and temporal specificity. Comprising a phased array transducer system of 1024 individually steered elements, the current clinical MRgFUS device can target brain regions with sub-millimetric accuracy, using real-time feedback for monitoring and intraoperative image guidance. In transgenic mouse models of AD, ultrasound was used to deliver antibodies against beta-amyloid and tau, with significant reductions in pathology and a positive impact on memory performance.

But we need to help humans and not mice, don’t we?
A study was conducted with five people, three men and two women with a mean age of 66.2 years. Four patients completed both the first and second stages of sonication. Patient 4 developed a respiratory illness unrelated to the procedure shortly before stage 2, and the doctors elected not to proceed with the second stage given the unknown risk of opening the BBB in the context of an active infection.

What were the results of this study?
The BBB was successfully opened in all patients who underwent the focused ultrasound procedure. White matter in the frontal lobe was primarily targeted, attempting to be specific to the dorsolateral prefrontal cortex where possible, given anatomic constraints. No patient experienced a serious adverse event during this study. There were no deaths, hemorrhages, swelling, or neurologic deficits on the day of procedure or during follow-up.

What does this figure show?

1. Baseline
2. Imediately after stage 2 sonication and blood–brain barrier (BBB) opening
3. At 24 h after procedure.

The circled element shows the contrast extravasation within the 10 × 10 × 7 mm3 sonicated volume in the right frontal lobe is seen immediately after the procedure, demonstrating increased BBB permeability. At 24 h after the procedure, there is no significant extravasation of contrast in the area, suggesting BBB closure

Okay, so why is this such a major discovery?
For the first time, safe, reversible, and repeated, non-invasive opening of the BBB using MRgFUS in patients with amyloid-positive AD had been demonstrated. BBB opening was achieved with less than 1% of the energy required to create a thermocoagulation (Process of surgical or laser based therapy for treating brain tumour and epilepsy), thereby enhancing the safety and expanding the treatment envelope of the procedure. No serious clinical or radiographic adverse events were observed, with progressively larger brain regions opened, and complete closure of the barrier within 24 h.

Is this study reliable enough?
As a matter of fact, it isn’t reliable enough. This study has several important limitations. First, the sample size is small, and although we provide evidence of clinical and radiographic safety, this limits generalizability. Second, the study was not designed to study efficacy, and we cannot draw conclusions about what effect, if any, focused ultrasound might have on the clinical symptoms of AD or on beta-amyloid clearance or deposition. Four enrolled patients were further under the age of 65, suggesting the possibility of earlier onset disease, distinct from sporadic AD. The relatively young age of enrolled patients may further affect generalizability given that prevalence of AD increases with age.