Professor Juhani Knuuti, MD, Turku PET Centre, Turku, Finland

The wisdom of water

By Philipp Grätzel von Grätz


Occasionally, technological progress opens the door for completely new realms of research. Such is the case at Turku PET Centre in Finland, where the Biograph Vision Quadra™ PET/CT is being used for total-body perfusion imaging—something that was simply not possible before.

Photography by Matti Immonen | Data courtesy of Turku PET Centre, Turku, Finland

PET imaging technology is very well suited to depict the function of a tissue. It does so by using radioactive substances, known as tracers. The best-known tracer is fludeoxyglucose injection F 18 (FDG), a sugar-molecule that is enhanced with the radionuclide fluorine-18. It accumulates in sugar-hungry cancer tissue and is widely used to detect metastases. PET can also be used to image tissue perfusion. This is called perfusion imaging. Here, the aim is not to measure the blood flow in the big blood vessels, but rather how much blood is actually available in the periphery, in the tissues of the heart, the muscles, or any other organ.

“The PET tracers most commonly used for cardiac perfusion imaging are rubidium and ammonia,” says Professor Juhani Knuuti, MD, from the PET Centre at Turku University. Rubidium is more comfortable to use, since it can be produced in a generator and does not require a particle accelerator, known as a cyclotron, on site. Both tracers have disadvantages, though, which is why Knuuti became interested in a different kind of tracer: radioactive water, or “radiowater.” That was back in 1993 when Knuuti wrote his doctoral thesis on PET imaging and used radiowater as a tracer: “The images were terrible.”

Patients are scanned on Biograph Vision Quadra with the radiowater bolus infusion to a vein and with simultaneous adenosine stress infusion

Patients are scanned on Biograph Vision Quadra with the radiowater bolus infusion to a vein and with simultaneous adenosine stress infusion (syringe in the foreground).  

Patient preparation is similar to any other perfusion study but radiowater delivery requires special equipment.

Patient preparation is similar to any other perfusion study but radiowater delivery requires special equipment.   

But terrible or not, the new tracer was there to stay. Radiowater is water that contains the isotope Oxygen-15 (15O). According to Knuuti, it has two distinct advantages over other tracers. “The clear benefit is that its half-life is short—only two minutes—meaning that the radiation dose for the patient becomes minimal. For a perfusion study, it is in the range of only 0.4 mSv, which is extremely low. You could basically repeat this examination as often as you liked without relevant risk.”

The second advantage of radiowater as a tracer is that it behaves like normal water. It is freely diffusible almost anywhere in the human body, making it—in theory—a nearly perfect tracer for perfusion images of the whole body. The downside of water’s diffusivity is that perfusion cannot be visualized in the same way as with other tracers. “We need to do sophisticated image processing, and in order to do that properly, we need sensitive scanners and powerful software.”

In the late 1990s and early 2000s, PET scanners became more sensitive. As a result, the images generated by water perfusion PET imaging became “less bad.” And this is how water as a tracer entered clinical routine, at least in some of the bigger PET centers with an on-site cyclotron— such as in Turku. “We started to use water in PET perfusion imaging of the heart routinely in 2005, and we have done thousands of scans since then,” says Knuuti. In the meantime, medtech companies started to combine their PET scanners with CT scanners, transforming PET imaging into PET/CT imaging, which can depict tissue function and body anatomy at the same time.

These days, the PET Centre in Turku is taking another leap forward. A new Siemens Healthineers Biograph Vision Quadra™ PET/CT scanner was installed in May 2022. Knuuti is convinced that it has started an exciting new era in the 30 years’ history of water perfusion imaging. “So far, we have only been able to image individual organs, for example the heart or the brain. With Biograph Vision Quadra and water as a tracer, we can capture all other organs additionally for free. This scanner is so sensitive that we can do total-body water perfusion imaging within four minutes, without extra radiation.”

Being able to analyze the perfusion in different parts of the body simultaneously is exciting because previously this was simply impossible, says Knuuti. “With total-body water perfusion imaging, we are entering a new field of research. There are extremely interesting questions that we can ask now, for example, about the impact of a disease on other parts of the body.” In an ongoing research project, experts from the Turku PET Centre are looking into patients with myocardial ischemia, a disease with reduced perfusion of the heart muscle due to atherosclerosis. “We have no idea what happens in the other organs of these patients, specifically the brain or the kidneys. With total-body water perfusion imaging, we can now simply take a look.”

Located downstairs at the Centre, the particle accelerator makes the radioactive water.

Located downstairs at the Centre, the particle accelerator makes the radioactive water.

The water is then pumped upstairs into the cylinder.

The water is then pumped upstairs into the cylinder.  

Another example: It is well known that the brain and the heart interact in many ways, even in healthy individuals. But how exactly? And what does that mean for the oxygen supply and the oxygen distribution in the body in different situations? The question becomes clinically relevant, according to Knuuti, in patients who receive pharmacological stressors for diagnostic procedures. “Some patients feel very bad after these pharmaceuticals. Our hypothesis is that this might be related to perfusion changes in the brain— which is why we are looking into that in another research project.”

Professor Juhani Knuuti, MD 

Total-body water perfusion can be used in other medical specialties, too. In oncology, for example, standard total-body examinations with PET/CT can visualize glucose uptake in cancer cells, using the tracer FDG. But it could also be interesting to visualize tumor perfusion on a large scale. “Nobody has done that before because it wasn’t possible. But let’s see—it is a different dimension of information.” Beyond total-body perfusion imaging with radiowater, Biograph Vision Quadra is also an interesting tool for research with other tracers. “In the European Biograph Vision Quadra consortium, different institutions use different types of tracers,” says Knuuti. Some institutions are taking advantage of the low radiation doses made possible by Biograph Vision Quadra. Others use metabolic tracers to produce metabolic “maps” of the body for diseases in a way that was simply not feasible before. 

Back to Turku: By end of February 2023, Knuuti and his team had already used total-body water perfusion imaging for more than 100 patients. Commercial water delivery devices are available to transfer the radiowater from the cyclotron swiftly to the patients. In terms of methodology, a mathematical modelling team is currently working on a segmentation software that relies heavily on artificial intelligence algorithms. “The idea is to automatically create a total-body perfusion map, so there is no need for any manual processing,” says Knuuti. This work is well under way, and once tools like these are available, totalbody water perfusion can be used in clinical routine. “I would be surprised if we didn’t have a deliverable product soon. What will take longer is to fully understand how to read the scans.”

Philipp Grätzel von Grätz lives and works as a freelance medical journalist in Berlin. His specialties are digitalization, technology, and cardiovascular therapy.

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