Use of PET imaging to combat Alzheimer’s disease

Dag Sehlin at the PET camera.

Dag Sehlin at the PET camera. It can be used to achieve an accurate diagnosis and also find out whether a drug works as intended.

Photograph: Mikael Wallerstedt

Alzheimer’s disease is one of the most common dementia disorders, but diagnosing and treating it still require a great deal of research. Scientists at Uppsala University are developing the PET technique to achieve an accurate diagnosis and also find out whether a drug works as intended.

A new treatment for Alzheimer’s disease (AD) is currently being tested at Uppsala University Hospital in a Phase 3 study. An antibody developed by researchers at Uppsala University is undergoing trials and further development by BioArctic, the Swedish biopharma company.

Simultaneously, the research group is developing a positron emission tomography (PET) ligand of the antibody to find traces of AD in the brain. There, as AD progresses, the protein beta amyloid forms clumps. It is precisely these abnormal protein accumulations of protein that the antibody seeks out.

Luring the antibody

Since antibodies are extremely large molecules, it is hard for them to cross the blood–brain barrier and penetrate the brain. The researchers therefore had to try using a stealthy method of getting the antibodies to enter in larger quantities.

“We added to the antibody an extra little molecule, a tiny protein domain that binds to a receptor in the blood–brain barrier. Using this molecule, the antibody enters the brain like a stowaway,” says Stina Syvänen.

“We increased the uptake of the antibody by a factor of almost 100, and then we suddenly had concentrations in the brain that enable us to use it with a PET camera.”

The modified antibody binds to a receptor in the wall of a blood vessel so that it is actively transported across the blood–brain barrier and into the brain, where it can bind to its target molecule, beta amyloid.

The PET camera depicts the brain and detects radioactivity. The scientists therefore carried out another modification of the antibody, tagging it with a small radioactive label. To date, the new PET ligand has been tested on mice and proved to bind to beta-amyloid in the brain.

More effective treatment and fewer side effects

Dag Sehlin thinks the new technique may also be useful for treating AD:

“The antibodies that are in clinical trials have now shown an effect in patients, but you have to administer them in extremely high doses. This can cause side effects and is also very expensive. Our hope is that if this antibody that gets into the brain is used much more effectively, it can lead to more effective treatment, with reduced side effects, at lower cost. In Sweden, on the other hand, there are over 100,000 Alzheimer’s patients and it would cost a fortune to treat them all.”

PET study using a modified, radiolabelled antibody that visualises the increase in beta amyloid with advancing age in Alzheimer’s mice.

It can be quite difficult for a doctor to assess whether a person suffering from memory problems has AD. With the new method, fairly early diagnosis would be possible – even before the patient has any symptoms. However, help is sought only when memory or orientation problems arise.

“By then, the disease has already been going on inside the brain for perhaps 15–20 years. This is the challenge: that patients really need to be treated before they feel they’re unwell. And that’s why it’s extremely important to have accurate and good diagnostic methods, so that we can detect the disease as soon as possible,” Sehlin says.

Measuring the drug’s effect

As early as the beginning of the 2000s, a PET ligand was developed. However, it targeted the protein’s hard core, which is more difficult to treat. With the new PET ligand, more soluble protein can be found instead. This is the form of beta amyloid that moves around in the brain.

By using the same antibody that can then be used for treatment, the scientists know that the antibody’s target molecule is actually present in the brain.

“The fact that it’s been so hard to develop Alzheimer’s medication is due to our lack of methods of measuring whether drugs in clinical trials have an effect. With PET imaging, you can see the brain before a treatment programme begins and, after a while, do it again to see whether the drug candidate has done what it should,” Syvänen says.

Sina Syvänen examines PET images at her computer, with Dag Sehlin in the background. Both are researchers at the Department of Public Health and Caring Sciences at Uppsala University.

However, before use of a PET ligand in humans can become a reality, a great deal of research is required. The receptor used to transport the antibody to the brain varies from one species to another, so what works in mice needs to be changed to work in humans. Moreover, the antibodies need to be modified so that they can disappear more rapidly from the body. This would make it possible to get an injection in the morning and be scanned with the PET camera on the same day.

“We must improve all these puzzle pieces first, before we can test the technique on humans. Just like all other research, it’s quite a slow process and you have to be very sure that what you end up injecting into people isn’t anything dangerous, and is also something effective,” Sehlin says.

Need set to increase

The research group at the Department of Public Health and Caring Sciences in Uppsala is among the world leaders in Alzheimer’s research. On the whole, Swedish research is at the forefront in this area. And one thing is certain: in the future, the need to be able to treat AD will only grow.

“We’re living longer and longer, and our treatments for cancer and heart disease are improving all the time. In the future, people will die from dementia to a greater extent because they’ll survive the other diseases. Age is by far the biggest risk factor for getting Alzheimer’s disease, so there’s a huge need,” Syvänen says.

Facts about the PET technique

  • As a method of diagnosing AD, positron emission tomography (PET) has developed rapidly in the past few years. During examination, a radioactive tracer is inserted in the patient’s body. With a PET camera, the researchers can then study the way in which this tracer is taken up and distributed in the body’s cells or organs.
  • The PET technique is particularly suited to diseases affecting the brain, since sampling brain issue is difficult. Imaging the brain, on the other hand, does no harm to the patient.

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