PET joins the fight against Alzheimer’s disease

Facts: PET scans

Positron emission tomography (PET) has developed rapidly over recent years as a method for diagnosing Alzheimer’s disease. During the examination, a radioactive marker, or radiotracer, is administered to the patient. A PET scanner can then follow the progress of this radiotracer as it is absorbed and distributed around the body’s cells or organs.

PET scans are especially well-suited to diseases of the brain, as it is difficult to collect samples inside the brain. Scanning the brain, however, does not harm the patient.

While Alzheimer’s disease is one of our most common de mentias, a great deal of research re mains to be done into met hods for diagnosing and treating the disease. Researchers at Uppsala University are developing positron emission tomography (PET) as a reliable diagnostic tool and as a means of determining the ef ficacy of a drug.

text ANNICA HULTH photo MIKAEL WALLERSTEDT

A NEW ALZHEIMER’S treatment is currently being tested at Uppsala University Hospital in a phase III study. The study is testing an antibody produced by researchers at Uppsala University and further developed by biopharma company BioArctic.

The research group is simultaneously developing the antibody into something called a PET ligand, which can detect traces of Alzheimer’s disease in the brain. This is possible because, in Alzheimer’s, the protein beta-amyloid accumulates in the brain. It is these protein accumulations that the antibody seeks out.

BECAUSE ANTIBODIES are such large molecules, they have difficulty crossing the blood-brain barrier into the brain. Researchers therefore needed to find a way for the antibody to trick its way into the brain in larger quantities.

“We added an extra molecule to the antibody, a small protein domain with the ability to bind to a receptor in the bloodbrain barrier. With its help, the antibody can enter the brain as a stowaway,” explains Stina Syvänen.

“We increased the uptake of the antibody by a hundredfold and then suddenly we had sufficient concentrations in the

Dag Sehlin, researcher at the Department of Public Health and Caring Sciences. “It has been difficult to develop Alzheimer’s drugs precisely because we have lacked methods to measure the efficacy of the drugs in clinical trials,” says Stina Syvänen, a researcher at the Department of Public Health and Caring Sciences.

brain to use it with a PET camera.”

As well as providing an image of the brain, the PET camera also detects radioactivity, so researchers made another modification to the antibody, tagging it with a small radiotracer. Thus far, the new PET ligand has been tested on mice and demonstrated the ability to bind to beta-amyloid in the brain.

DAG SEHLIN BELIEVES that this new technology may also prove useful in treating the disease.

“Although the antibodies currently undergoing clinical trials have demonstrated efficacy in patients, they have to be prescribed in very high doses. This can lead to side effects and is also very expensive. We hope that by using this antibody, which can enter the brain much more effectively, we can achieve a more effective treatment with fewer side effects, at a lower cost. In Sweden alone there are over 100,000 Alzheimer’s patients and, were one to treat them all, it would entail enormous costs.”

It can be quite difficult for a doctor to assess whether or not someone suffering memory lapses has Alzheimer’s disease. Using the new method it should be possible to diagnose the disease at a fairly early stage, even before the patient is displaying any symptoms. But, of course, it is only when problems such as memory loss or orientation difficulties arise that people seek help.

“By then the disease may have already been present in the brain for 15–20 years. This presents a challenge with the treatment itself; one would actually need to begin to treat the patient before they have any idea that they’re sick. This is why accurate and reliable diagnostic methods are so important, so that the disease can be detected as early as possible,” says Sehlin.

ALTHOUGH THE FIRST PET ligand dates back to the early 2000s, this targeted the water-insoluble core of the protein, which is more difficult to treat. The new PET ligand targets the more soluble protein, the form of beta-amyloid that moves around in the brain.

By using the same antibody for diagnosis and treatment, one can be sure that the antibody’s target molecule is actually in the brain.

“It has been difficult to develop Alzheimer’s drugs precisely because we have lacked methods to measure the efficacy of the drugs in clinical trials. By using PET, we can image the brain before commencing a treatment programme and once again after a while, so we can see whether the drug is having the desired effect,” says Syvänen.

HOWEVER, THERE IS a good deal of research to be conducted before the PET ligand can be used in humans. The receptor used to transport the antibody to the brain differs from species to species, so a procedure that works in mice will require alteration to work in humans. Antibodies will also need to be modified to disappear from the body more quickly. You can then be injected in the morning and have a PET scan on the same day.

“We need to improve all of these pieces of the puzzle before we can

conduct trials on humans. Just like any other research, this is a drawn-out process and one must be very sure that, when the time comes to inject people, they receive something that is both nonhazardous and effective,” says Sehlin.

THE RESEARCH GROUP at the Department of Public Health and Caring Sciences in Uppsala is a global leader in Alzheimer’s research. Swedish research in general is at the forefront of this field and one thing is certain: the need to treat Alzheimer’s disease will only increase over the coming years.

“We are living longer and longer and have better and better treatments for cancer and cardiovascular diseases. In future, more people will die of dementia because they have survived these other diseases. Age is by far the greatest risk factor for Alzheimer’s disease so the need is enormous, ” says Syvänen. ●

PET study using modified, radiolabeled antibodies to visualise the increase in beta-amyloid production with aging in Alzheimer mice.

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