Neuroimaging Techniques in the Diagnosis of Glioma

The functioning of an MRI machine
This video gives a brief description of the physics of an MRI machine.
It describes the phenomenon of nuclear magnetic resonance, and how it's
manipulated to produce 3D images.
Video from: [4]

Neuroimaging techniques are one of the most important diagnostic tools used by physicians for the clinical assessment of brain tumors. They are usually integral to the initial evaluation and assessment of brain tumors in patients, and with modern advances in technology, they can sometimes provide a non-­‐invasive method of diagnosis. Advanced methods of Magnetic resonance spectroscopy have also been shown to be able to differentiate between various forms of glioma subtypes, which could further aid diagnosis [1]. Furthermore, certain studies have demonstrated novel or advanced imaging techniques which allow for much improved delineation of Glioma margins, a useful tool for treatment evaluation and surgical guidance [2] . Hence, the importance of developing new, or modifying existing neuroimaging techniques cannot be understated.

Susceptibility-Weighted Magnetic Resonance Imaging

Magnetic Resonance Imaging

Magnetic Resonance Imaging techniques revolve around the detection of excited hydrogen protons within the tissue of the are being imaged. These protons possess a characteristic that is shared with many subatomic particles: spin. Since these protons are charged, their spin generates the smallest of magnetic fields, giving the protons a magnetic moment. When the protons are exposed to an external magnetic field, their magnetic moments begin to wobble, and they align with the external magnetic field, producing longitudinal magnetization. The rate at which these spins wobble is termed the Larmor frequency, and is directly proportional to the strength of the magnetic field. The application of a strong radiofrequency pulse causes the longitudinal magnetization vector to rotate by 90 degrees, putting the protons in an excited state. This creates a magnetic resonance signal that can be detected by a receiver coil. The contrast in MR images arises from the differences in the relaxation time (the time it takes for the proton to return to equilibrium) between normal and diseased tissue [3]. However, other molecules can be exogenously introduced into the body during an MRI scan to enhance contrast between normal and diseased tissue[5].

Susceptibility Weighted Enhancement

Susceptibility weighted imaging (SWI) is a new form of Magnetic Resonance Imaging which exploits variations in the magnetic susceptibility between different tissues to form images[5].SWI is also referred to as blood oxygen dependent venographic imaging (BOLD imaging), since it can detect the susceptibility difference between oxygenated blood and deoxygenated blood with extremely high sensitivity. When blood is oxygenated, the iron atom at the core of the hemoglobin molecule behaves as a material which is repelled by a magnetic field (diamagnetic), and contrastingly, when blood is deoxygenated, it the iron atom in hemoglobin is attracted by magnetic fields (paramagnetic). Initially, this allowed for SWI to be used in the study of functional changes in brain activity through changes in blood flow to certain areas of the brain. However, SWI can also be used to visualize differences in local blood oxygenation levels that are associated with neuro-pathologies, such as metabolically active tumors. The angiogenic property of tumors drives increased blood supply and blood volume to the cancerous tissue, allowing for the visualization of the blood vessel patterns which form around malignant tumors. Furthermore, the ability to detect deoxygenated blood in the microvascularity could allow for non-invasive differentiation of Low grade, benign tumors from High grade malignant tumors[6]. Determining the angiogenic ability of a tumor is an important factor in determining its malignancy, and is a core criterion for their histological assessment, and grading. This imaging technique allows this aspect of tumors to be analyzed in a lot of depth, and with extremely high sensitivity. For instance, SWI can detect differences in the relative cerebral blood volume, which is much lower intralesionally in low grade-gliomas, and higher in anaplastic astrocytomas and glioblastoma multiforme[7].

18F-Fluoro-Ethyl-Tyrosine Positron Emission Topography

MRI and 18F-FET PET Brain Scan of a 47 Year Old Patient who has
undergone Malignant Transformation of a Low Grade Glioma
Image Unavailable
The images above show MR (top brain scan), 18F-FET (bottom brain scan), and histological staining (A,B, C, D)
of a Low Grade glioma that has developed into a High Grade glioma. The PET scans show an increase in the uptake of
18F-FET as the tumour becomes more malignant, making it a good indicator of tumour grade. On the left, histological
staining with Hematoxylin and eosin show a grade 2 diffuse astrocytoma (A) and MIB-1 staining (B) indicates low
proliferation of tumour cells. On the right,histological staining with Hematoxylin and eosin show a grade 3
astrocytoma (C) and MIB-1 staining (D) indicates increased proliferation.
Picture from: [15]

Positron Emission Topography

Positron Emission Topography (PET) scans have become increasingly popular among neuro-oncologists since they can provide information regarding the metabolic state of the tumor, unlike conventional MRI or CT scans. This information, along with providing more accurate diagnosis, can also be used for patient management, and the evaluation of treatments. Positron emission topography is a technique which produces three dimensional images by detecting an exogenously introduced radiolabelled tracer molecule, and is able to depict functional processes in the body[1]. The technique works by indirectly detecting positrons which are emitted from the nucleus of the radiolabelled tracer molecule. When a positron is emitted from the molecule it travels a short distance in the tissue before colliding with an electron, resulting in the formation of a pair of photons which travel in opposite directions. The photons are detected by detector plates which are in the bulk of the machine surrounding the scanning region. When two photons travelling in opposite directions reach the detector plate at the same time, a line of response is formed connecting the two points on the detector plate. Computer analysis of many lines of response allow for the formation of a 3D image[8].

18F-Fluoro-Ethyl-Tyrosine As a Tracer Molecule

Avery useful tracer for the assessment of brain tumors is 18F-Fluoro-ethyl-tyrosine (18F-FET), since its uptake into tissues has been significantly correlated with various properties of malignant tumors, such as: neoangeogenesis, cell density, proliferation rate, and microvascular density. It has also been observed that tumors which observed no contrart enhancement in MRI scans had specific 18F-FET uptake, suggesting that there are specific mechanisms regulating the its uptake into tumors[9] . The uptake of 18F-FET into tissues has been sugessted to involve the amino acid transporter system L, a family of heterodimeric transmembrane transport proteins. More specifically it is thought that the three transport proteins LAT1, LAT2, and LAT3 are responsible for the uptake of 18F-FET into tumour cells[10]. (expand on this) It has also been found that the uptake of 18F-FET is less in inflammatory cells arising due to infection, than in tumor cells. This can help with the differentiation between lesion that have occurred due to infection and those that are due to a tumor[11] . 18F-FET has also been shown to be very accurate at classifying tumor grades, and was able to correctly identify 95% of high grade tumors, and 88% of low grade tumors. Furthermore, 18F-FET was found to be able to detect brain tumors with extremely high sensitivity, regardless of whether the tumor came from non glial or glial origins, and has even been shown to be able to differentiate between various histopathologies that are present within the same lesion with 82% specificity and 92% sensitivity10. Combining FET scans with other MR techniques can also improve the diagnostic identification of gliomas up to 97% sensitivity, and is a very effective method of non-invasively differentiating between tumour tissues[9].
In addition to 18F-FET, 18F-fluorothymidine has been found to be a very effective tracer molecule for the imaging of brain tumors. 18F-fluorothymidine is actively incorporated into replicating DNA, and hence is incorporated into cells that are proliferating, which is a characteristic of malignant tumours [8].

MRI-Photoacoustic-Raman imaging (MPR) nanoparticles

For information on the use of Iron Oxide nanoparticles in treatment, click here:nanotechnology-in-glioblastoma-multiforme

Triple modality MPR concept for patient management
nano particle
Image Unavailable
 Top: an image of the MPR nano particle, and a representation of its accumulation
within tumour cells,and its inability to cross an intact blood-brain barrier
Bottom: a series of images that illustrate a method of application of the triple modality concept.
In this case, the MPR nano particles are administered once, since they are retained within the
tumor cells for a very long time. Preoperatively, an MRI scan is done for surgical planning.
Raman imaging and Photoacoustic imaging are utilized intraoperatively for surgical guidance.
Finally Raman imaging is used postoperatively to make sure the tumor has been completely removed.
Picture from: [2]
one another.  

A recent study by Kircher et al demonstrated a novel method of neuroimaging using a specific nanoparticle that can be detected by three different imaging modalties which include: surface enhanced Raman scattering (SERS), Photoacoustic imaging, and MRI. The technique involves the sequential use of all three modalities to detect the nanoparticles, forming an overall picture that is composed of three images (one from each modality) superimposed upon each other, allowing for a very high resolution image, with well defined tumour boundries[2].

Photoacoustic imaging

Photoacoustic imaging is a relatively new technique that works by detecting ultrasound waves produced by excited molecular targets within the body. Non-ionizing pulses of light are emitted into the tissue, and are absorbed by the MPR nanoparticles, causing them to thermally expand, culminating in the production of ultrasonic waves. The ultrasonic waves then detected by an ultrasonic sensor, which analyze the time difference between the emission of the light pulse and the detection of the ultrasound wave to create a 3D image of the distribution of MPR nanoparticles within the tissue[2]. Photoacoustic imaging is one of the best imaging techniques available today for the visualization of deeper lying tissue due to its ability to take images with high spatial resolution. Thus photoacoustic imaging could be used to locate tumor tissue that is lying under normal brain tissue, or even to guide gross resections, with Raman imaging beung used sequentially to remove the microscopic tumour deposits[12].

Raman Imaging

Raman Imaging is an optical technique which relies on the Raman light scattering effect, that measures the inelastic reflection of light rays. When light interacts with an object, some of the reflected rays are at a lower energy level than the incident ray, have a longer wavelength, and are called in-elastically scattered rays[13]. One of the most important advancements, which allowed Raman imaging to be applied clinically, was the discovery of the surface enhanced Raman scattering (SERS) effect. The SERS effect arises due to an increase in the incident electromagnetic field surrounding molecules which been attached to a metallic nanoparticle. This increases the Raman effect significantly, making it much easier to detect accurately. Kircher et al. found that Raman imaging was able to detect the nanoparticles at picomolar sensitivity, making it the most sensitive out of the three imaging modalitites. Furthermore, the molecular tag for Raman imaging which is on the nanoparticles provide a signature signal, which is unique to the MPR, and hence there is very little background signal, making Raman imaging highly specific.

Guidance of tumor removal surgery using Raman Imaging
Image Unavailable
 The series of pictures at the top show the removal of a brain tumor in a mouse, with overlay of Raman images
to help guide the procedure. Once the tumour was grossly removed, Raman imaging showed that there were still signals
from MPR's coming from the tumor area. Assessment of the area with histological stains revealed that there were still
cancerous cells present, and demonstrated the high sensitivity and specificity of Raman Imaging.
Picture from: [2]  

Magnetic Resonance imaging with MPR Nanoparticles

As contrast agents for MRI scans, the MPR nanoparticles are superior to others (such as gadolinium based contrast agents) in the fact that stay within the cancerous tissue for much longer period of time and hence can be used for preoperative analysis, as well as intraoperative guidance with one round of administration. Other contrast agents that are of lower molecular weight are usually cleared from the body much faster. In areas where the blood-brain-barrier has broken, these other contrast agents leak into the extracellular space, and where it can rapidly diffuse through the interstitial fluid, and be excreted by the renal system. The localization of these contrast agents can also reduce the precision of the MRI scan, and can lead to false positives, which could be very damaging to the patient[2].

The MPR Nanoparticle

The nanoparticle itself is composed of a 60nm gold core, covered by a layer of trans-1,2-bis(4-pyridyl)-ethylene, the molecular tag for RAMAN imaging, and its outer layer is covered with a protective silica coating. Another distinguishing fact about the nanoparticles is that the inert gold core and silica coating are non-cytotoxic, unlike many other nanoparticles, making it more applicable for clinical use. The kinetics of the uptake of the MPR nanoparticles in to tumors is based upon the enhanced retention and permeability effect (EPR). Which retains the nanoparticles within the tumor for long periods of time, and at high concentrations. EPR arises in tumors due to their angiogenic and proliferative properties. The blood vessels that develop to supply the tumor with blood are extremely permeable due to the production of inflammatory agents such as prostaglandins, and permeability enhancers such as Nitric Oxide and bradykinin [14].

1. Hutterer, M., Nowosielski, M., Putzer, S. [18F]-fluoro-ethyl-l-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma. Neuro Oncol. 15, 341-351 (2013
2. Kircher, M.F. de la Zerda, A. Jokerst, J.V. “A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle” Nat Med. 18(5):829-34 (2012)
3. Weishaupt, D., Köchli, V. D., Marincek , B. How Does MRI Work? An Introduction to the Physics and Function of Magnetic Resonance Imaging. Springer-Verlag. Germany (2006)
4. How does an MRI work? 31/3/14
5. El-Koussey, M., Schenk, P., Kiefer, C. Susceptibility weighted imaging of the brain: does gadolinium administration matter. European Journal of Radiology. 82, 272-276 (2012)
6. Reichenbach, J. R, Haacke, E. M. High-resolution BOLD venographic imaging: a window into brain function. NMR Biomed. 14, 453-467 (2001)
7. Ramano, A., Espagnet, M. C. R., Calabria, L. F. clinical applications of dynamic susceptibility contrast perfusion-weighted MR imaging in brain tumors. Radiol Med. 117, 455-460 (2012)
8. La Fougere, C., Suchorska, B., Bartenstein, P. Molecular imaging of gliomas with PET: opportunities and limitations. Neuro oncol. 13, 806-819 (2011)
9. K. J. Langen, K. Hamacher, M. Weckesser et al., “O-(2-[18F]fluoroethyl)-l-tyrosine: uptake mechanisms and clinical applications,” Nuclear Medicine and Biology, vol. 33, no. 3, pp. 287–294, (2006)
10. Dunet, V., Rossier, C., Buck, A. Performance of 18F-Fluoro-Ethyl-Tyrosine (18F-FET) PET for the Differential Diagnosis of Primary Brain Tumor: A Systematic Review and Metaanalysis. J Nucl Med. 53, 207-214 (2012)
11. Kunz M, Thon N, Eigenbrod S, et al. Hot spots in 18FET-PET delineate malignant tumor parts within suspected WHO grade II glioma. Neuro Oncol (2011);13:307-316.
12. de la Zerda, A. et al. Photoacoustic ocular imaging. Opt. Lett. 35, 270–272 (2010)
13. Zavaleta, C.L., Kircher, M.F. & Gambhir, S.S. Raman's “effect” on molecular imaging. J. Nucl. Med. 52, 1839–1844 (2011)
14. Maeda, H., Wu, J., Sawa, T., Matsumura, Y. & Hori, K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Release 65, 271–284 (2000)
15. Galldiks N1, Stoffels G, Ruge MI. Role of O-(2-18F-fluoroethyl)-L-tyrosine PET as a diagnostic tool for detection of malignant progression in patients with low-grade glioma. J Nucl Med. 54(12):2046-54 (2013)

Add a New Comment
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License