(Study type: Nuclear scan; related body system: Circulatory, digestive, nervous systems.)

Positron emission tomography (PET) combines the biochemical properties of nuclear medicine with the anatomical accuracy of computed tomography (CT). PET uses positron emissions from specific radionuclides. The positron radiopharmaceuticals generally have short half-lives, ranging from a few seconds to a few hours; therefore, they must be produced in a cyclotron located near where the test is being done. A radionuclide is basically composed of a measurable radioactive isotope and a biologically active molecule. The isotopes are derived from elements that are either naturally present in organic molecules (oxygen, nitrogen, and carbon) or can be substituted for naturally occurring elements (fluorine can be substituted for hydrogen). Selected molecules become biologically active radiolabeled analogs of their naturally occurring forms to create radionuclides that produce detailed functional images of the target organ’s structure. Radionuclides are used to evaluate many aspects of organ function, including oxygen consumption and glucose metabolism; most PET studies are conducted in the areas of cardiology, neurology, and oncology. The studies are used to diagnose and stage diseases as well as to monitor the efficacy of therapeutic interventions.

During the PET scan, the radiotracer is injected into the body where it migrates to the intended target organ, becomes involved in the physiological process of interest, and accumulates to the degree that radioactive emissions are detected by the PET scanner. The PET scanner translates the emissions from the radioactivity as the positron combines with the negative electrons from the tissues and forms gamma rays that can be detected by the scanner. This information is transmitted to the computer, which determines the location and its distribution and translates the emissions as color-coded images for viewing, quantitative measurements, activity changes in relation to time, and three-dimensional computer-aided analysis.

Major organs such as the brain, heart, and cardiac muscles and anatomical areas with high concentrations of tissue such as the pelvis, use oxygen and glucose almost exclusively to meet their energy needs; therefore, their metabolism has been studied widely with PET. Each radionuclide tracer is designed to measure a specific body process, such as glucose metabolism, blood flow, and brain or cardiac tissue perfusion. Flourine-18, in the form of fluorodeoxyglucose (FDG), is one of the most versatile and commonly used radionuclides in PET. FDG is a glucose analogue. All cells use glucose, but diseases that involve increased metabolic activity will show a high level of radionuclide visualization, whereas those that are hypometabolic will show little to no radionuclide visualization. There is little localization of FDG in normal tissue with minimal amounts being evenly distributed, allowing rapid detection of abnormal disease states. The radionuclide can be administered by IV injection or inhaled as a gas.

Brain

After the radionuclide becomes concentrated in the brain, PET images of blood flow or metabolic processes at the cellular level can be obtained. Oxygen-15 is used in circumstances that warrant the evaluation of blood flow in the brain to predict or identify areas affected by a stroke. PET scan of the brain has had the greatest clinical impact in patients with epilepsy, dementia, neurodegenerative diseases, inflammation, cerebrovascular disease (indirectly), and brain tumors. There is a substantial campaign to develop better, less invasive markers of neurodegenerative diseases of the brain as well as to develop personalized treatments such as drug targets—and potentially a means of prevention. When a reliable disease dependent marker or target is identified (e.g., a cellular process or essential chemical messenger) novel therapeutics can be developed to disrupt the disease process at the molecular level. Alzheimer disease (AD) is the most common neurodegenerative disease and Parkinson disease (PD) the second most common. Imaging modalities and biomarkers in blood, cerebrospinal fluid (CSF), and skin tissue are used to assist in the diagnosis of AD and PD.

Alzheimer Disease

At one point in time, AD could be diagnosed only upon autopsy. Diagnostic and treatment options have significantly improved. PET imaging has been considered the gold standard for supporting the diagnosis of AD. Although PET is still a mainstay, it is invasive, expensive, and not universally available. Newer tests can be performed on either CSF or blood. CSF specimen collection is an invasive procedure performed via lumbar puncture and carries the potential for more postprocedural complications than a venipuncture. Development of reliable blood-based tests have been awaited for many years. Two biomarkers have produced a rapidly growing number of different testing platforms for both blood and CSF: beta-amyloid 42/40 ratios and tau proteins.

• Note: Not all tests are available in every state, are covered by insurance, or are approved by the U.S. Food and Drug Administration (FDA). Laboratory test results vary by method and facility; patient result reporting and interpretation are provided by the testing laboratory.
• Imaging. Florbetaben F 18 (Neuraceq), florbetapir F 18 (Amyvid), and flutemetamol F18 (Vizamyl) are examples of FDA-approved radionuclides for PET scans to image and estimate beta-amyloid plaque density.
• Imaging. Flortaucipir F 18 (Tauvid) is an FDA-approved radionuclide for PET scans to image and estimate tau neurofibrillary tangle density and distribution.
• Blood or CSF—beta-amyloid 42/40 ratio. Beta-amyloid is produced by a variety of cells such as astrocytes, fibroblasts, neuroblastoma cells, neurons, and platelets. It circulates in the plasma portion of blood, CSF, and brain interstitial fluid, mainly in the soluble form of beta-amyloid 40 (AB40). AB40 and beta-amyloid 42 (AB42) are both found in brain plaques; AB42 is the more prevalent form in brain plaques. The first tests developed were CSF-based assays. Blood-based assays have now become available. The ratio of AB42/AB40from blood or CSF samples is used to indicate risk of AD. A cutoff is determined for each specific method; a lower ratio than the cutoff indicates a potential diagnosis of AD. The actual physiological role of beta-amyloid is an active topic of research. An adjunctive test often requested to support the increased risk of developing AD is identification of apolipoprotein E variants from a blood sample to identify carriers of the APOE₄ gene sequence variation, also associated with AD.
• Blood or CSF—tau proteins. Normal tau protein is a structurally supportive component in nerve cells (neurons) of the brain. Abnormal, phosphorylated forms of tau “stick” to other tau proteins and form neurofibrillary tangles believed to be strongly associated with AD. CSF and blood-based tests have been developed to measure two types of tau protein, phosphorylated (pTau–217) and unphosphorylated (npTau-217); a ratio is used to demonstrate the correlation between increased abnormal tau proteins and AD (pTau-217)/(npTau-217).
• Research in the area of neurodegenerative diseases is active and continuously developing. For example, pTau-181 is emerging as a potentially better biomarker when used in a ratio with AB42. The AB42/AB40 ratio, pTau-181/AB42 ratio, and pTau-217 quantitative tests provide evidence of the two main types of Alzheimer pathology: amyloid plaques and tau tangles. The pTau-181/AB42 ratio also demonstrates consistent agreement with amyloid PET scans in assessing the presence of amyloid deposits. PET scans provide significant structural and functional information in real time; they provide information related to neuronal and synaptic loss (neurodegeneration), the third main type of Alzheimer pathology. For additional information regarding CSF biomarkers, refer to the study titled “Alzheimer Disease Markers.”
• January 6, 2023, the FDA-approved lecanemab-irmb (Leqembi), a new treatment for AD in the confirmed presence of beta-amyloid.

Parkinson Disease

PD is a complicated disease with no single diagnostic test; the diagnosis requires information provided in the patient’s medical and family history, description of symptoms, presentation of signs, and a thorough neurological examination. Research conducted with PET scanning, using a variety of tracers, can assess different characteristics of the complex pathology associated with neurodegenerative diseases such as PD. For example, uptake of the radiotracer fluorine-18-dihydroxyphenylalanine (F-18-DOPA) by specific brain neurons indicates the level of dopamine production; dopamine is an essential neurotransmitter and hormone involved in many functions, including memory and motor function. Research has demonstrated that decreased uptake correlates with worsening of signs and symptoms such as bradykinesia and rigidity that are considered hallmarks of PD. PET scanning with a different tracer, F-18–FDG, can differentiate between PD (normal or increased uptake) and multiple system atrophy (decreased uptake). The Parkinson’s Foundation’s website noted that up to 70% of individuals with PD will develop dementia as their disease advances; studies conducted with the F-18–FDG PET have demonstrated the tracer’s ability to differentiate between patients with PD with early to significant dementia (decreased functionality in cortical area of the brain) and those without dementia. A number of tests are already available from an authorized HCP, while others are in the research stage of development. Methods used to assist in the diagnosis of PD include the following:

• Note: Not all tests are available in every state, are covered by insurance, or are FDA approved.
• Imaging. The dopamine transporter scan (DaTscan) became FDA approved in 2011. It uses SPECT (single-photon emission computed tomography) to visualize the degree of function in the dopamine system of the brain after injection of the radiotracer ioflupane I-123. The test cannot distinguish between PD and other neurodegenerative disorders.
• Imaging. MRI (brain). For additional information, refer to the study titled, “Magnetic Resonance Imaging, Various Sites (Brain).”
• Skin Biopsy examination. The Syn-One Test involves collection of three skin biopsies (posterior cervical region of the back/neck, lower thigh, lower leg above the ankle), application of an immunofluorescence assay method and examination of the samples by a pathologist for the presence of a protein called alpha-synuclein. As with the DaTscan, presence of the protein is not diagnostic for PD. The Syn-One Test demonstrated detection of alpha-synuclein in 95% of patients with synucleinopathy. Synucleinopathy is a group of neurodegenerative disorders that includes PD, Lewy body dementia, multiple system atrophy, and pure autonomic failure.
• Blood. The Mito DNA_DX is a polymerase chain reaction (PCR)–based assay that identifies damaged mitochondrial DNA from a blood sample. The research team’s results demonstrated that elevated levels of damaged mitochondrial DNA were observed in people with PD compared to people without PD. It is hoped the assay will not only be able to diagnose PD and monitor PD but also assist in developing drugs to treat PD.
• Cerebrospinal fluid (CSF). Research is being conducted regarding a group of techniques known as seed amplification assays (SSA). Alpha-synuclein SSA identifies misfolded alpha-synuclein in the CSF, olfactory mucosa, saliva, salivary glands, and skin of people with neurodegenerative disorders such as PD. The technique is believed to have the potential to differentiate between the various neurodegenerative disorders. This would be a significant advance over the currently available studies.

Heart

Cardiac PET scans are used to diagnose coronary artery disease (CAD), identify areas of heart tissue that are dead or scarred as a result of a myocardial infarction, and identify areas of impaired or diminished blood flow that may be corrected with coronary angioplasty/stent or coronary artery bypass surgery. For additional information regarding screening guidelines for atherosclerotic cardiovascular disease (ASCVD), refer to the study titled “Cholesterol, Total and Fractions.”

Pelvic

Detection of colorectal tumor, staging of various types of tumors, evaluation of the effects of therapy, detection of recurrent disease, and detection of metastases are the main reasons to do a pelvic PET scan. PET/CT is useful in identifying sites of metastatic ovarian cancer.