Ultrasound 'breakthrough' in treating Alzheimer's

"Alzheimer's breakthrough as ultrasound successfully treats disease in mice," The Guardian reports.

New research found high-energy sound waves helped remove abnormal clumps of proteins from the brains of mice, and also improved their memory.

The mice used in this study were genetically engineered to produce amyloid plaques – abnormal clumps of protein fragment amyloid-β typically found in the brains of people with Alzheimer's disease.

There was a 50% reduction in plaques in mice whose brains were exposed to ultrasound once a week for five to seven weeks.

Memory also improved to the extent that the mice were able to negotiate a maze as well as healthy mice after the treatment. They were also better able to avoid a section of a spinning wheel that would give them an electric shock.

While the treated mice appeared to be unharmed, with no obvious tissue damage, human brains are much more complex. Ultrasound could damage brain function in ways that we cannot predict.

The current study used mice that have plaques, but not the other two main brain features of Alzheimer's: cell damage and loss of neural connections. Both these differences limit our certainty of how well the findings represent what would happen in humans. Therefore, further animal studies are needed.

Where did the story come from?

The study was carried out by researchers from the University of Queensland in Australia and was funded by the estate of Dr Clem Jones AO, the Australian Research Council, and the National Health and Medical Research Council of Australia.

The study was published in the peer-reviewed journal Science Translational Medicine.

The Guardian reported the story accurately and indicated that this is very early stage research, with human trials unlikely to occur for several years. It was encouraging that the newspaper's headline made it clear that the study was on mice, rather than humans.

What kind of research was this?

This was an animal study, which aimed to see if ultrasound showed potential for use as a treatment for Alzheimer's disease.

When ultrasound of the brain is combined with an injection of tiny spheres (microbubbles) into the blood, it temporarily makes it easier for substances to cross the blood-brain barrier (the membrane that separates the two). This might help the removal of amyloid-β from the brain and stop the build-up of plaques.

Alzheimer's disease is the most common form of dementia. The cause is unknown, but there are three main features of the disease in the brain. They are:

a build-up of amyloid plaques, which are deposits of a protein fragment called amyloid-β
neurofibrillary tangles, which are abnormal collections of a protein called tau in the nerve cells
loss of connections between the nerves

Previous research has aimed to reduce the amyloid plaques using drugs to decrease the production of amyloid-β or increase its removal by the immune system. Drugs used in both ways have had side effects.

Here, the researchers wanted to see if ultrasound could be used to reduce the amyloid plaques and whether this improved memory. A mouse model of Alzheimer's disease was used for their experiments.

Animal models are used for the early testing of potential treatments for the human form of the disease. These tests are essential for assessing the potential beneficial effects and safety of these treatments before they are used in humans.

However, there are differences between species, and between disease models and the actual human disease. This means results in animal models may not perfectly represent what will happen in humans.

Alzheimer's is a complex disease, and there are several mouse models of this condition, each with slightly different features of the disease. The mouse model used in this study developed amyloid plaques, but not neurofibrillary tangles or loss of connections between the nerves.

What did the research involve?

Twenty mice genetically engineered to develop amyloid plaques in their brains were given either five sessions of ultrasound over six weeks, or sham (placebo) treatment.

The sham treatment involved receiving the microbubble injection and being placed under the ultrasound machine, but not receiving any ultrasound. Both groups were then assessed for their spatial working memory using a maze.

The researchers compared 20 mice with amyloid plaques and 10 normal mice using the active place avoidance task. This involves mice getting an electric shock if they enter a particular zone in a rotating arena. Mice with amyloid plaques did not learn to avoid this area as well as control mice with no plaques.

The amyloid mice were then put into two groups. One group received ultrasound every week for seven weeks, and the other group had a sham treatment. The mice were then retested in the active place avoidance task.

After these tests, their brains were inspected for amyloid plaques. The researchers also carried out various tests to see how ultrasound might be having an effect on plaques.

What were the basic results?

The mice with amyloid plaques did not perform as well on the maze task as healthy mice. However, ultrasound restored the ability of the mice to negotiate the maze to the same level as normal mice.

When the researchers compared the brains of the two groups of mice, they found ultrasound reduced the amount of amyloid plaques by over half.

Mice treated with ultrasound weekly for seven weeks learned to avoid electric shocks in the active place avoidance task better than mice given sham treatment, indicating that their memory had improved. They also had half the amount of amyloid plaques in their brains as the untreated mice.

Ultrasound appeared to have stimulated microglial cells (brain support cells that get rid of waste) to engulf the amyloid-β to reduce the plaques. The treatment did not appear to cause any tissue damage.

How did the researchers interpret the results?

The researchers concluded that repeated ultrasound to the entire mouse brain reduced the amyloid plaques and improved the memory of the mice.

They say this has the potential to treat conditions such as Alzheimer's disease, though there are many hurdles to overcome.

Conclusion

This animal study found a technique using ultrasound directed at the brain reduces the number of amyloid plaques in mice. These mice were genetically engineered to develop these plaques, one of the key brain features of Alzheimer's disease.

There are two other features of Alzheimer's disease that these mice did not have: neurofibrillary tangles and loss of nerve connections.

As it is unknown how these features inter-relate, or if one causes another, this model has certain limitations.

However, the results did show that by reducing the amount of amyloid plaques, the memory and spatial awareness of the mice improved.

While mice studies can give us an indication of how a treatment may affect humans, they are only indications, as there are inherent differences between the species, and between the model and the actual human disease.

Although we can study the mice's ability to negotiate a maze and avoid electric shocks, it is more difficult to assess higher and more complex human brain functions that are affected in Alzheimer's, such as language and personality.

The authors pointed out several important differences between this mouse study and the ability to use the technique in humans:

The human brain is much larger, and the skull thicker, so the ultrasound would need to be stronger to penetrate all areas of the brain. This could have negative consequences, such as causing damage to healthy brain tissue.
There are concerns that the level of immune response that might be activated in the human brain could be too high. To counter this, the researchers suggest the potential treatment regimen could focus on giving ultrasound to smaller sections at a time.
The mice in the study already had plaques when the ultrasound was started. The researchers do not know at what point of Alzheimer's disease it would be appropriate to start treating humans. They are concerned that if they gave ultrasound to people with very early Alzheimer's disease when there are few amyloid plaques, it may damage brain tissue.
The study did not look at the long-term effects of the treatment.

Further animal studies will now be required, progressing to primates, before any human trials can take place.

The cause of Alzheimer's disease is not known, but you can reduce the risk of developing the condition by adopting a healthy lifestyle, including maintaining a healthy weight, not smoking, taking regular physical exercise, and drinking alcohol in moderation.