Brain positron emission tomography

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Brain positron emission tomography
PET Normal brain.jpg
PET scan of a normal brain
ICD-10-PCS C030

Brain positron emission tomography is a form of positron emission tomography (PET) that is used to measure brain metabolism and the distribution of exogenous radiolabeled chemical agents throughout the brain. PET measures emissions from radioactively labeled metabolically active chemicals that have been injected into the bloodstream. The emission data from brain PET are computer-processed to produce multi-dimensional images of the distribution of the chemicals throughout the brain. [1] : 57 

Contents

Process

The positron emitting radioisotopes used are usually produced by a cyclotron, and chemicals are labeled with these radioactive atoms. The radioisotopes used in clinics are normally 18F (fluoride), 11C (carbon) and 15O (oxygen). The labeled compound, called a radiotracer or radioligand, is injected into the bloodstream and eventually makes its way to the brain through blood circulation. Detectors in the PET scanner detect the radioactivity as the compound charges in various regions of the brain. A computer uses the data gathered by the detectors to create multi-dimensional (normally 3-dimensional volumetric or 4-dimensional time-varying) images that show the distribution of the radiotracer in the brain following the time. Especially useful are a wide array of ligands used to map different aspects of neurotransmitter activity, with by far the most commonly used PET tracer being a labeled form of glucose, such as fluorodeoxyglucose (18F). [2]

Advantages and disadvantages

The greatest benefit of PET scanning is that different compounds can show flow and oxygen, and glucose metabolism in the tissues of the working brain. These measurements reflect the amount of brain activity in the various regions of the brain and allow to learn more about how the brain works. PET scans were superior to all other metabolic imaging methods in terms of resolution and speed of completion (as little as 30 seconds), when they first became available. The improved resolution permitted better study to be made as to the area of the brain activated by a particular task. The biggest drawback of PET scanning is that because the radioactivity decays rapidly, it is limited to monitoring short tasks. [1] : 60 >

Uses

Images obtained with PET (axial sections) that show the effects of chronic drug exposure on various proteins involved in dopamine (DA) neurotransmission and on brain function (as assessed by brain glucose metabolism). While some effects are common to many drugs of abuse,...others are more specific. These include the decrease...in brain monoamine oxidase B (...the enzyme involved in DA metabolism) in cigarette smokers. The rainbow scale was used to code the PET images; radiotracer concentration is displayed from higher to lower as red > yellow > green > blue. PET - Human Addiction.jpg
Images obtained with PET (axial sections) that show the effects of chronic drug exposure on various proteins involved in dopamine (DA) neurotransmission and on brain function (as assessed by brain glucose metabolism). While some effects are common to many drugs of abuse,...others are more specific. These include the decrease...in brain monoamine oxidase B (...the enzyme involved in DA metabolism) in cigarette smokers. The rainbow scale was used to code the PET images; radiotracer concentration is displayed from higher to lower as red > yellow > green > blue.

Before the use of functional magnetic resonance imaging (fMRI) became widespread, PET scanning was the preferred method of functional (as opposed to structural) brain imaging, and it still continues to make large contributions to neuroscience. PET scanning is also useful in PET-guided stereotactic surgery and radiosurgery for treatment of intracranial tumors, arteriovenous malformations and other surgically treatable conditions. [4]

PET scanning is also used for diagnosis of brain disease, most notably because brain tumors, strokes, and neurondegenerative diseases (such as Alzheimer's disease and Parkinson's disease) all cause great changes in brain metabolism, which in turn causes detectable changes in PET scans. PET is probably most useful in early cases of certain dementias (with classic examples being Alzheimer's disease and Pick's disease) where the early damage is too diffuse and makes too little difference in brain volume and gross structure to change CT and standard MRI images enough to be able to reliably differentiate it from the "normal" range of cortical atrophy which occurs with aging (in many but not all) persons, and which does not cause clinical dementia.

PET is also actively used for multiple sclerosis and other acquired demyelinating syndromes, but mainly for research into pathogenesis instead of diagnosis. They use specific radioligands for microglial activity. Currently is widely used the 18-kDa translocator protein (TSPO). [5] Also combined PET-CT are sometimes performed. [6]

Tracer Types

PET imaging with oxygen-15 indirectly measures blood flow to the brain. In this method, increased radioactivity signal indicates increased blood flow which is assumed to correlate with increased brain activity. Because of its 2-minute half-life, O-15 must be piped directly from a medical cyclotron for such uses, which is difficult.

PET imaging with 18F-FDG takes advantage of the fact that the brain is normally a rapid user of glucose. Standard 18F-FDG PET of the brain measures regional glucose use and can be used in neuropathological diagnosis.

The development of a number of novel probes for noninvasive, in vivo PET imaging of neuroaggregate in human brain has brought amyloid imaging to the doorstep of clinical use. The earliest amyloid imaging probes included 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP) [10] developed at the University of California, Los Angeles and N-methyl-[11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole [11] (termed Pittsburgh compound B) developed at the University of Pittsburgh. These amyloid imaging probes permit the visualization of amyloid plaques in the brains of Alzheimer's patients and could assist clinicians in making a positive clinical diagnosis of AD pre-mortem and aid in the development of novel anti-amyloid therapies. [11C]PMP (N-[11C]methylpiperidin-4-yl propionate) is a novel radiopharmaceutical used in PET imaging to determine the activity of the acetylcholinergic neurotransmitter system by acting as a substrate for acetylcholinesterase. Post-mortem examination of AD patients have shown decreased levels of acetylcholinesterase. [11C]PMP is used to map the acetylcholinesterase activity in the brain, which could allow for pre-mortem diagnoses of AD and help to monitor AD treatments. [12] Avid Radiopharmaceuticals has developed and commercialized a compound called florbetapir that uses the longer-lasting radionuclide fluorine-18 to detect amyloid plaques using PET scans. [13]

Dedicated Brain PET Devices

NeuroLF - a dedicated brain PET system. Photo courtesy of Positrigo AG, Switzerland NeuroLF.jpg
NeuroLF - a dedicated brain PET system. Photo courtesy of Positrigo AG, Switzerland

In 2019 Catana et al. [14] published an overview article about the "Development of Dedicated Brain PET Imaging Devices: Recent Advances and Future Perspectives". Various companies worldwide are working on developing a dedicated brain PET system either for pure research and/or clinical routine use. One of these companies is Positrigo which is working on the NeuroLF system.

Challenges

One main challenge for developing new PET tracers for neuroimaging is that these tracers must cross the blood-brain barrier. Commonly, small molecules which are fat soluble have been used as they can pass the blood-brain barrier through lipid mediated passive diffusion.

However, as pharmaceutics move towards large biomolecules for therapies, new research has also focused on using biomolecules, such as antibodies, for PET tracers. These new larger PET tracers have increased difficulty passing the BBB as they are too large to passively diffuse across. Therefore, recent research is investigating methods to carry biomolecules across the BBB using endogenous transport systems including carrier-mediated transporters such as glucose and amino acid carriers, receptor-mediated transcytosis for insulin or transferrin. [15]

Related Research Articles

<span class="mw-page-title-main">Positron emission tomography</span> Medical imaging technique

Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body. For example, 18
F
-FDG is commonly used to detect cancer, NaF18
F
 is widely used for detecting bone formation, and oxygen-15 is sometimes used to measure blood flow.

<span class="mw-page-title-main">Single-photon emission computed tomography</span> Nuclear medicine tomographic imaging technique

Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera, but is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.

A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by tracing the path that the radioisotope follows from reactants to products. Radiolabeling or radiotracing is thus the radioactive form of isotopic labeling. In biological contexts, use of radioisotope tracers are sometimes called radioisotope feeding experiments.

A radioligand is a radioactive biochemical substance, in particular, a ligand that is radiolabeled. Radioligands are used for diagnosis or for research-oriented study of the receptor systems of the body, and for anti-cancer radioligand therapy.

Pittsburgh compound B (PiB) is a radioactive analog of thioflavin T, which can be used in positron emission tomography scans to image beta-amyloid plaques in neuronal tissue. Due to this property, Pittsburgh compound B may be used in investigational studies of Alzheimer's disease.

Fluorodeoxyglucose (<sup>18</sup>F) Chemical compound

[18F]Fluorodeoxyglucose (INN), or fluorodeoxyglucose F 18, also commonly called fluorodeoxyglucose and abbreviated [18F]FDG, 2-[18F]FDG or FDG, is a radiopharmaceutical, specifically a radiotracer, used in the medical imaging modality positron emission tomography (PET). Chemically, it is 2-deoxy-2-[18F]fluoro-D-glucose, a glucose analog, with the positron-emitting radionuclide fluorine-18 substituted for the normal hydroxyl group at the C-2 position in the glucose molecule.

<span class="mw-page-title-main">Neuroimaging</span> Set of techniques to measure and visualize aspects of the nervous system

Neuroimaging is the use of quantitative (computational) techniques to study the structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive manner. Increasingly it is also being used for quantitative research studies of brain disease and psychiatric illness. Neuroimaging is highly multidisciplinary involving neuroscience, computer science, psychology and statistics, and is not a medical specialty. Neuroimaging is sometimes confused with neuroradiology.

<span class="mw-page-title-main">DASB</span> Chemical compound

DASB, also known as 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, is a compound that binds to the serotonin transporter. Labeled with carbon-11 — a radioactive isotope — it has been used as a radioligand in neuroimaging with positron emission tomography (PET) since around year 2000. In this context it is regarded as one of the superior radioligands for PET study of the serotonin transporter in the brain, since it has high selectivity for the serotonin transporter.

Perfusion is the passage of fluid through the lymphatic system or blood vessels to an organ or a tissue. The practice of perfusion scanning is the process by which this perfusion can be observed, recorded and quantified. The term perfusion scanning encompasses a wide range of medical imaging modalities.

Avid Radiopharmaceuticals is an American company, founded by Dr. Daniel Skovronsky, and based at the University City Science Center research campus in Philadelphia, Pennsylvania. The company has developed a radioactive tracer called florbetapir (18F). Florbetapir can be used to detect beta amyloid plaques in patients with memory problems using positron emission tomography (PET) scans, making the company the first to bring to market an FDA-approved method that can directly detect this hallmark pathology of Alzheimer's disease.

Florbetaben, a fluorine-18 (18F)-labeled stilbene derivative, trade name NeuraCeq, is a diagnostic radiotracer developed for routine clinical application to visualize β-amyloid plaques in the brain. It is indicated for Positron Emission Tomography (PET) imaging of β-amyloid neuritic plaque density in the brains of adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment. β-amyloid is a key neuropathological hallmark of AD, so markers of β-amyloid plaque accumulation in the brain are useful in distinguishing AD from other causes of dementia. The tracer successfully completed a global multicenter phase 0–III development program and obtained approval in Europe, US and South Korea in 2014.

Metabolic trapping refers to a localization mechanism of synthesized radiocompounds in the human body. It can be defined as the intracellular accumulation of a radioactive tracer based on the relative metabolic activity of the body's tissues. It is a basic principle of the design of radiopharmaceuticals as metabolic probes for functional studies or tumor location.

<span class="mw-page-title-main">Dihydrotetrabenazine</span> Chemical compound

Dihydrotetrabenazine or DTBZ is an organic compound with the chemical formula C19H29NO3. It is a close analog of tetrabenazine. DTBZ and its derivatives, when labeled with positron emitting isotopes such as carbon-11 and fluorine-18, are used as PET radioligands for examining VMAT2.

<span class="mw-page-title-main">Jacob Hooker</span>

Jacob M. Hooker is an American chemist and expert in molecular imaging, particularly in the development and application of simultaneous MRI and PET. He has contributed major advances on the entire spectrum of research from fundamental chemistry methodology with radioisotopes to human neuroimaging.

Fluciclovine (<sup>18</sup>F) Chemical compound

Fluciclovine (18F), also known as anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid, or as Axumin, is a diagnostic agent indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels.

Arterial input function (AIF), also known as a plasma input function, refers to the concentration of tracer in blood-plasma in an artery measured over time. The oldest record on PubMed shows that AIF was used by Harvey et al. in 1962 to measure the exchange of materials between red blood cells and blood plasma, and by other researchers in 1983 for positron emission tomography (PET) studies. Nowadays, kinetic analysis is performed in various medical imaging techniques, which requires an AIF as one of the inputs to the mathematical model, for example, in dynamic PET imaging, or perfusion CT, or dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Flortaucipir (<sup>18</sup>F) Chemical compound

Flortaucipir (18F), sold under the brand name Tauvid, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) imaging to image the brain.

<span class="mw-page-title-main">Julie C. Price</span> American physicist and professor of radiology

Julie C. Price is an American medical physicist and professor of radiology at Massachusetts General Hospital (MGH), Harvard Medical School (HMS), as well as the director of PET Pharmacokinetic Modeling at the Athinoula A. Martinos Center at MGH. Price is a leader in the study and application of quantitative positron emission tomography (PET) methods. Prior to this, Price worked with Pittsburgh colleagues to lead the first fully quantitative pharmacokinetic evaluations of 11C-labeled Pittsburgh compound-B (PIB), one of the most widely used PET ligands for imaging amyloid beta plaques. As a principal investigator at MGH, Price continues work to validate novel PET methods for imaging biological markers of health and disease in studies of aging and neurodegeneration, including studies of glucose metabolism, protein expression, neurotransmitter system function, and tau and amyloid beta plaque burden.

Hartmuth Christian Kolb is a German chemist. He is considered one of the founders of click chemistry.

References

  1. 1 2 Nilsson LG, Markowitsch HJ (1999). Cognitive Neuroscience of Memory. Seattle: Hogrefe & Huber Publishers. p. 57.
  2. ↑ Vallabhajosula, Shankar (2009). Molecular imaging: radiopharmaceuticals for PET and SPECT. Springer-Verlag. ISBN   978-3-540-76735-0. OCLC   437345781.[ page needed ]
  3. ↑ Volkow ND, Fowler JS, Wang GJ (May 2003). "The addicted human brain: insights from imaging studies". The Journal of Clinical Investigation. 111 (10): 1444–51. doi:10.1172/jci18533. PMC   155054 . PMID   12750391.
  4. ↑ Levivier, Marc; Massager, Nicolas; Wikler, David; Lorenzoni, José; Ruiz, Salvador; Devriendt, Daniel; David, Philippe; Desmedt, Françoise; Simon, Stéphane; Houtte, Paul Van; Brotchi, Jacques; Goldman, Serge (1 July 2004). "Use of Stereotactic PET Images in Dosimetry Planning of Radiosurgery for Brain Tumors: Clinical Experience and Proposed Classification". Journal of Nuclear Medicine. 45 (7): 1146–1154. PMID   15235060.
  5. ↑ Airas L, Nylund M, Rissanen E (March 2018). "Evaluation of Microglial Activation in Multiple Sclerosis Patients Using Positron Emission Tomography". Frontiers in Neurology. 9: 181. doi: 10.3389/fneur.2018.00181 . PMC   5879102 . PMID   29632509.
  6. ↑ Malo-Pion C, Lambert R, Décarie JC, Turpin S (February 2018). "Imaging of Acquired Demyelinating Syndrome With 18F-FDG PET/CT". Clinical Nuclear Medicine. 43 (2): 103–105. doi:10.1097/RLU.0000000000001916. PMID   29215409.
  7. ↑ Nasu, Seiji; Hata, Takashi; Nakajima, Tooru; Suzuki, Yutaka (May 2002). "Evaluation of 18F-FDG PET in acute ischemic stroke: assessment of hyper accumulation around the lesion". Kaku Igaku. 39 (2): 103–110. OCLC   111541783. PMID   12058418. NAID   10025136171.
  8. ↑ Derdeyn, Colin P.; Videen, Tom O.; Simmons, Nicholas R.; Yundt, Kent D.; Fritsch, Susanne M.; Grubb, Robert L.; Powers, William J. (August 1999). "Count-based PET Method for Predicting Ischemic Stroke in Patients with Symptomatic Carotid Arterial Occlusion". Radiology. 212 (2): 499–506. doi:10.1148/radiology.212.2.r99au27499. PMID   10429709.
  9. ↑ Read, S. J.; Hirano, T.; Abbott, D. F.; Sachinidis, J. I.; Tochon-Danguy, H. J.; Chan, J. G.; Egan, G. F.; Scott, A. M.; Bladin, C. F.; McKay, W. J.; Donnan, G. A. (1 December 1998). "Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole". Neurology. 51 (6): 1617–1621. doi:10.1212/WNL.51.6.1617. PMID   9855512. S2CID   34075.
  10. ↑ Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, et al. (December 2001). "Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer's disease". The Journal of Neuroscience. 21 (24): RC189. doi:10.1523/JNEUROSCI.21-24-j0004.2001. PMC   6763047 . PMID   11734604.
  11. ↑ Mathis CA, Bacskai BJ, Kajdasz ST, McLellan ME, Frosch MP, Hyman BT, et al. (February 2002). "A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain". Bioorganic & Medicinal Chemistry Letters. 12 (3): 295–8. doi:10.1016/S0960-894X(01)00734-X. PMID   11814781.
  12. ↑ Kuhl, D.E.; Koeppe, R.A.; Minoshima, S.; Snyder, S.E.; Ficaro, E.P.; Foster, N.L.; Frey, K.A.; Kilbourn, M.R. (1 March 1999). "In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease". Neurology. 52 (4): 691–699. doi:10.1212/wnl.52.4.691. PMID   10078712. S2CID   11057426.
  13. ↑ Kolata, Gina (24 June 2010). "Promise Seen for Detection of Alzheimer's". The New York Times.
  14. ↑ Catana, Ciprian (2019). "Development of Dedicated Brain PET Imaging Devices: Recent Advances and Future Perspectives". Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 60 (8): 1044–1052. doi:10.2967/jnumed.118.217901. PMC   6681695 . PMID   31028166.
  15. ↑ Sehlin D, Syvänen S (December 2019). "Engineered antibodies: new possibilities for brain PET?". European Journal of Nuclear Medicine and Molecular Imaging. 46 (13): 2848–2858. doi:10.1007/s00259-019-04426-0. PMC   6879437 . PMID   31342134.
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