Article: Positron emission tomography

Image of a typical positron emission tomography (PET) facility

Positron emission tomography (PET) is a nuclear medicine medical imaging technique which produces a three dimensional image or map of functional processes in the body.

Description

Maximum Intensity Projection (MIPS) of a typical ¹⁸F-FDG wholebody PET acquisition

Schema of a PET acquisition process

Schematic view of a detector block and ring of a PET scanner (here: Siemens ECAT Exact HR+)

A short-lived radioactive tracer isotope which decays by emitting a positron, chemically incorporated into a metabolically active molecule, is injected into the living subject (usually into blood circulation). There is a waiting period while the metabolically active molecule (usually a sugar) becomes concentrated in tissues of interest, then the subject is placed in the imaging scanner. The short-lived isotope decays, emitting a positron. After travelling up to a few millimeters the positron annihilates with an electron, producing a pair of annihilation photons (similar to gamma rays) moving in opposite directions. These are detected when they reach a scintillator material in the scanning device, creating a burst of light which is detected by photomultiplier tubes. The technique depends on simultaneous or coincident detection of the pair of photons: photons which do not arrive in pairs (i.e., within a few nanoseconds) are ignored.

The most significant fraction of electron-positron decays result in two 511keV photons being emitted at almost 180 degrees to each other, hence it is possible to localise their source along a straight line of coincidence. In practice the line of coincidence has a finite width as the emitted photons are not exactly 180 degrees apart. Using statistics collected from tens-of-thousands of coincidence events, a map of their origin in the body can be plotted. The resulting map shows the tissues in which the molecular probe has become concentrated, and can be interpreted by nuclear medicine physician or radiologist in the context of the patient's diagnosis and treatment plan. PET scans are increasingly read alongside CT scans or MRI scans, the combination giving both anatomic and metabolic information (what the structure is, and what it is doing). PET is used heavily in clinical oncology (medical imaging of tumors and the search for metastases) and in human brain and heart research.

Because PET imaging is most useful in combination with anatomical imaging, such as CT, modern PET scanners are now available with integrated high-end multi-detector-row CT scanners. Because the two scans can be performed simultaneously, not only is time saved, but the two sets of images are precisely registered so that areas of abnormality on the PET imaging can be correlated with anatomy on the CT images.

Alternative methods of scanning include x-ray computed tomography (CT), magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI), ultrasound and single photon emission computed tomography (SPECT).

However, while other imaging scans such as CT and MRI, isolate organic anatomic changes in the body, PET scanners are capable of detecting areas of molecular biology detail (even prior to anatomic change) via the use of radiolabelled molecular probes that have different rates of uptake depending on the type of tissue involved. The changing of regional blood flow in various anatomic structures (as a measure of the injected positron emitter) can be visualized and relatively quantified with a PET scan.

PET imaging is best performed using a dedicated PET scanner. However, it is possible to acquire PET images using a conventional dual-head gamma camera fitted with a coincidence detector. The quality of gamma-camera PET is considerably lower, and acquisition is slower. However, for institutions with low demand for PET, this may allow on-site imaging, instead of referring patients to another center, or relying on a visit by a mobile scanner.

Radionuclides used in PET scanning are typically isotopes with short half lives such as ¹¹C (~20 min), ¹³N (~10 min), ¹⁵O (~2 min), and ¹⁸F (~110 min). Due to their short half lives, the radionuclides must be produced in a cyclotron at or near the site of the PET scanner. These radionuclides are incorporated into compounds normally used by the body such as glucose, water or ammonia and then injected into the body to trace where they become distributed. Such labelled compounds are known as radiotracers.

PET as a technique for scientific investigation in humans is limited by the need for clearance by ethics committees to inject radioactive material into participants, and also by the fact that it is not advisable to subject any one participant to too many scans. In neurological research, this limitation can be partly overcome by the use of short-lived radionuclides that result in a lower radiation dose. PET also has an expanding role in the assessment of response to therapy, and in particular cancer therapy (e.g. Young et al. 1999).

PET is also used in pre-clinical studies using animals, where it allows repeated investigations into the same subjects. This is particularly valuable in cancer research, as it results in an increase in the statistical quality of the data (subjects can act as their own control) and very substantially reduces the numbers of animals required for a given study. A further limitation arises from the high costs of cyclotrons needed to produce the short-lived radionuclides for PET scanning (for example ¹⁸F). Few hospitals and universities are capable of maintaining such systems, and most clinical PET is supported by third-party suppliers of radio-tracers which can supply many sites simultaneously. This limitation restricts clinical PET primarily to the use of tracers labelled with ¹⁸F, which has a half life of 110 minutes and can be transported a reasonable distance before use, or to ⁸²Rb, which can be created in a portable generator and is used for myocardial perfusion studies.

Applications

PET is a valuable technique for some diseases and disorders, because it is possible to target the radio-chemicals used for particular bodily functions.

1. Oncology: PET scanning with the tracer (¹⁸F) fluorodeoxyglucose (FDG, FDG-PET) is widely used in clinical oncology. This tracer is a glucose analog that is taken up by glucose-using cells and phosphorylated by hexokinase (whose mitochondrial form is greatly elevated in rapidly-growing malignant tumours). Because the oxygen atom replaced by ¹⁸F to generate FDG is required for the next step in glucose metabolism in all cells, no further reactions occur. Furthermore, most tissues (with the notable exception of liver and kidneys) cannot remove the phosphate added by hexokinase. This means that FDG is trapped in any cell which takes it up, since phophorylated sugars (due to their ionic charge) cannot exit from the cell. This results in intense labeling of tissues with high glucose uptake, such as the brain, the liver, and most cancers. As a result FDG-PET can be used for diagnosis, staging, and monitoring treatment of cancers, particularly in Hodgkin's disease, non Hodgkin's lymphoma, and lung cancer. However because individual scans are more expensive than conventional imaging with CT and MRI, expansion of FDG-PET in cost-constrained health services will depend on proper Health Technology Assessment. Oncology scans using FDG make up over 90% of all PET scans in current practice.
2. Neurology: PET neuroimaging is based on an assumption that areas of high radioactivity are associated with brain activity. What is actually measured indirectly is the flow of blood to different parts of the brain, which is generally believed to be correlated, and has been measured using the tracer oxygen (¹⁵O). However, because of its 2-minute half-life ¹⁵O must be piped directly from a medical cyclotron for such uses, and this is difficult. In practice, since the brain is normally a rapid user of glucose, and since brain pathologies such as Alzheimer's disease greatly decrease brain metabolism of both glucose and oxygen in tandem, standard FDG-PET of the brain (which measures regional glucose use) may also be successfully used to differentiate Alzheimer's disease from other dementing processes, and also to make early diagnosis of Alzheimer's disease. The advantage of FDG-PET for these uses is its much wider availability.

   Several radiotracers have been developed for PET that are ligands for specific neuroreceptor subtypes (e.g. dopamine D2, serotonin 5-HT1A, etc.) or enzyme substrates (e.g. 6-FDOPA for the AADC enzyme). These agents permit the visualization of neuroreceptor pools in the context of a plurality of neuropsychiatric and neurologic illnesses. A novel probe developed at the University of Pittsburgh termed PIB (Pittsburgh Compound-B) permits the visualization of amyloid plaques in the brains of Alzheimer's patients. This technology could assist clinicians in making a positive clinical diagnosis of AD pre-mortem and aid in the development of novel anti-amyloid therapies.

3. Cardiology: In clinical cardiology FDG-PET can identify so-called "hibernating myocardium", but its cost-effectiveness in this role versus SPECT is unclear.
4. Neuropsychology / Cognitive neuroscience: To examine links between specific psychological processes or disorders and brain activity.
5. Psychiatry: Numerous compounds that bind selectively to neuroreceptors of interest in biological psychiatry have been radiolabeled with ¹¹C or ¹⁸F. Radioligands that bind to dopamine receptors (D1,D2, reuptake transporter), serotonin receptors (5HT1A, 5HT2A, reuptake transporter) opioid receptors (mu) and other sites have been used successfully in studies with human subjects. Studies have been performed examining the state of these receptors in patients compared to healthy controls in schizophrenia, substance abuse, mood disorders and other psychiatric conditions.
6. Pharmacology: In pre-clinical trials, it is possible to radio-label a new drug and inject it into animals. The uptake of the drug, the tissues in which it concentrates, and its eventual elimination, can be monitored far more quickly and cost effectively than the older technique of killing and dissecting the animals to discover the same information. PET scanners for rats and apes are marketed for this purpose. Drug occupancy at the purported site of action can also be inferred indirectly by competition studies between unlabeled drug and radiolabeled compounds known apriori to bind with specificity to the site.

PET scans safety

PET scanning is non-invasive, but it does involve exposure to ionizing radiation. The total dose of radiation is small, however, usually around 7 mSv. This can be compared to 2.2 mSv average annual background radiation in the UK, 0.02 mSv for a chest X-Ray, up to 8 mSv for a CT scan of the chest, 2-6 mSv per annum for aircrew, and 7.8 mSv per annum background exposure in Cornwall (Data from UK National Radiological Protection Board).

Because the half-life of ¹⁸F is about two hours, the prepared doses decay significantly during the working day. If the FDG is delivered to the scanning suite in the morning, the specific activity falls during the day, and a relatively larger volume of radiopharmaceutical must be injected in later patients to deliver the same radioactive dose.

See also

• antimatter
• functional neuroimaging
• neuroimaging
• SPECT (Single Photon Emission Computed Tomography)
• statistical parametric mapping