���߲ݴ�ý

It’s one of the final frontiers in biomedical research: how to target and treat brain disease.

Now, Professor Isabelle Aubert of the ���߲ݴ�ý’s department of laboratory medicine and pathobiology has found a new way to address this age-old challenge. 

Aubert, who is also a senior scientist at Sunnybrook Research Institute (SRI), is using a technology developed by fellow SRI researcher Dr. Kullervo Hynynen to overcome the blood-brain barrier, a densely layered filter that lines the brain’s blood vessels. While this barrier protects the brain from toxins, infections and other threats, it also blocks drugs from treating brain diseases. 

To overcome this barrier, Aubert and her colleagues use MRI-guided focused ultrasound to increase the blood vessels' permeability, allowing drugs to pass through and target the brain. Remarkably, even without drugs, it seems that focused ultrasound has the ability to heal the brain.

She describes how this technology works and how it could impact future treatment. 

How does MRI-guided focused ultrasound work for delivering drugs to the brain?
We use MRI to visualize the part of the brain we want to treat. We then inject microbubbles into the bloodstream and use focused ultrasound to make the microbubbles vibrate in selected areas of the brain. This energy temporarily increases the permeability of the blood-brain barrier, and when we inject therapeutics into the bloodstream we can target specific areas of the brain.  After treatment, the blood-brain barrier restores its properties within a few hours.

What has your latest research revealed?
We’ve been studying how this technology can deliver drugs to treat Alzheimer’s disease, and the results have been very promising in our mouse models. When we targeted parts of the brain with ultrasound and antibodies, we found that we could reduce amyloid-beta plaques, a hallmark of Alzheimer’s disease. 

We also discovered that using ultrasound and microbubbles alone reduces amyloid-beta plaques. We have evidence that this technology further stimulates glial brain cells (astrocytes and microglia) to capture more amyloid-beta and help clear plaques. Natural antibodies in the blood (IgG and IgM) can also enter targeted brain regions, where they bind amyloid-beta and clear it from the brain.

More recently, we found that focused ultrasound increased the number of new neurons in the hippocampus, a brain region involved in learning and memory. It’s exciting when you realize that you can stimulate the brain to repair itself using ultrasound technology on its own. This approach also led to improved memory in a mouse model of Alzheimer’s disease.

Why is Alzheimer’s disease so difficult to treat?
Alzheimer’s disease is complex – we do not know its cause, and it is difficult to diagnose early. It can start devastating the brain decades before we can detect memory problems. Furthermore, most drugs can barely pass through the blood-brain barrier. This includes expensive antibodies – only 0.1 per cent of antibodies can pass through this barrier. This is where ultrasound technology can become very useful.

How could your discoveries change patient treatment?
Focused ultrasound, in different ways than the ones mentioned here, has already revolutionized the way patients with essential tremors are treated.

Our discoveries provide evidence that we could change the way patients with neurodegenerative disorders are treated in the future. We could tailor and improve our treatments for different patients and diseases by combining focused ultrasound with an intravenous therapeutic, which would enter the brain at targeted areas. Ultrasound stimulation and drug delivery to the brain don’t involve surgery, so there’s a minimal risk of infection – it has the potential to decelerate disease and accelerate patients’ recovery.

It’s really exciting to think of the ways it could impact many types of diseases.  

Your research is highly collaborative. Who else is working with you?
is the pioneer in focused ultrasound. We also work closely with for her expertise in Alzheimer’s disease and its treatment. I’m a neurobiologist and I research how ultrasound can not only reduce disease but also repair the brain and restore its function. By combining our expertise, we can look at the whole picture – from understanding how this technology works to how it can treat disease and stimulate the brain to repair itself.  

What are your next steps?
Our results are very promising and we are now evaluating the ideal treatment for Alzheimer’s disease. In our animal models, we are studying how long the beneficial effects of ultrasound last and how we can improve this treatment in combination with other therapeutics. These could include drugs, cells or genes. 

Above: ultrasound vibrates microbubbles injected into the blood, allowing the natural antibodies IgG and IgM, as well as glial cells – astrocytes and microglia – to clear amyloid-beta from the brain. This technology also promotes brain regeneration by stimulating the growth of new neurons.

(Illustration by Dr. Emmanuel Thévenot/lab of Dr. Isabelle Aubert; courtesy of Sunnybrook Research Institute.) 

More U of T research into Alzheimer's disease:

Katie Babcock is a writer with the Faculty of Medicine at the ���߲ݴ�ý.