Exogenous and Endogenous Tracers in Perfusion Weighted Imaging - Essay Example

? Exogenous and Endogenous tracers in perfusion-weighted imaging (PWI) Introduction Perfusion weighted imaging isa new technique in clinical applications used to detect ischemic stroke. It can be used to detect microvascular perfusion malfunctions and abnormalities as well as to assess blood flow to the brain parenchyma or to a vascular bed. In this technique, blood parameters (haemodynamic quantities) such as blood volume, blood flow, and the average time taken by a tracer molecule to traverse the tissue (mean transit time) can be assayed using exogenous tracers such as gadolinium or endogenous tracers such as arterial blood. A tracer by definition can be either histochemical, isotopic, radioactive, dye, mercuric or ammunition used for tracing purposes or to analyze the composition of organs, tissues or cells with regards to clinical applications. This research paper highlights the usage of both exogenous and endogenous tracers in perfusion weighted imaging (PWI), the differences and similarities between the two methods, the clinical significance or applications of the two methods and how to obtain the final perfusion information (Wintermark et al., 2005). Exogenous Tracers PWI using exogenous tracers such as gadolinium depends on the magnetic receptiveness or susceptibility and effects of inflow to acquire haemodynamic information. In this technique, gadolinium obtained from gadolinium diethyltriaminepentaacetate (Gd-DTPA) compound is injected into the venous system resulting into a transient loss of signal when the tracer perfuses thorough the tissues or cells which is then followed by magnetic resonance imaging (MRI). The tracer Gd-DTPA being paramagnetic causes a difference in susceptibility to exist between the capillaries carrying gadolinium and the neighbouring tissues. As a result, a strong field gradient is created in the walls of surrounding vessels which in turn causes the direct signal to dephase in gradient echo images and the mediated diffusion to dephase in spin echo images. The experienced signal loss (S) due to passage of gadolinium can be expressed as: S = S?e-TE?R2. In this expression, S? refers to the signal observed in the absence of contrast agent, TE stands for echo time (regulates time T2), and ?R2 refers to the difference in relaxation due to tracer (gadolinium) and is directly proportional to the concentration of the tracer in the tissue given by CT. This leads to the equation: ?R2 = k х CT in which k as a constant depends on the field strength, pulse sequence used and tissue type. Gd-DTPA and other contrast agents have a number of applications such as in lesion enhancements and MR angiography where the time T1 utilizes the shortening effects of the tracer gadolinium which is paramagnetic. In such applications, contrast agents such as Gd-DTPA gives increased signal. Research shows that the tracer gadolinium can be assayed either by T2* or T1 contrast. However, T2 contrast is mostly used in assays involving brain perfusion images and on the other hand, cardiac perfusion studies are assayed by changes in T1. Passage of an exogenous tracer can as well be followed using gradient or spin echo sequences. Spin echo PWI is characterized by appearance of reduced form of a large vessel and is more of a representative of perfusion in capillary. On the other hand, gradient echo PWI shows a higher disparity to noise ratios. It is worth noting that PWI is totally dependent on a sequence with good temporal resolution. Rapid image acquisition techniques such as EPI sequence or parallel imaging while maintaining a spatial resolution and volume coverage are essential if a high temporal resolution is to be achieved. Gd-DTPA is administered as a bolus of in short venous injection lasting only for a short duration (few seconds) after which it is allowed to increase is width and it eventually reaches the target organ within 10seconds or longer. As the dynamic passage is followed, several image volumes are also acquired within the same time. This process guarantees the acquisition of multi-slice images of the organ in not more than 2 seconds. Therefore, EPI is the most preferred sequence to others as it has the ability to acquire the whole of k-space with one 90 excitatory pulse (Lorenz, 2004). Tracer Kinetics Haemodynamic information such as blood volume, mean transit time, and blood flow can be obtained from the analyses majored on tracer kinetics. The theory of tracer kinetics was developed in the 19thcentury (Thomas, Oridge & Taylor, 2009). In its applications such as DSC-MRI was first described in 1991 by Rosen et al, the theory holds on a number of assumptions which are: No pooling or leakages of fluid or blood takes place No additional sources of tracer or blood/fluid other than the input Perfusion remains constant and tracer does not alter it Tracer is vigorously blended with blood hence both the tracer and the blood flows together Rose et al used rapid measurements of MRI signal change after the injection of a bolus of a paramagnetic MRI contrast agent. From her work, it is realized that quantification of BV, BF and MTT, requires that regional changes in signal intensity with respect to time be converted into curves of contrast agent concentration time. Estimation of BV within a given voxel is calculated from the area under the curve of contrast concentration and the width of the contrast bolus gives the MTT estimate of blood passing through the voxel. The regional BF can then be calculated using the following equation: BF = BV?MTT This figure shows the relationship between residual function and the hemodynamic properties. It is evident that as the tracer passes through the tissue, signal loss increases, and the intensity normalizes as the tracer passes out the tissue. The degree of signal loss due to the passage of Gd-DTPA depends on two factors: The concentration of the injected tracer in the blood and the volume of intravascular blood or fluid within the tissue of interest, and it can be expressed by the following equation: S= S0 e-TE?R2 ?R2=1/T2post-contrast - 1/T2pre-contrast And that ?R2 = k x CT .The desired concentration can be calculated with respect to the s signal. The realized concentration change is subject to the residual function R(t) . R(t) is defined as the amount of residual tracer in the tissue at any time or the rate of flow through the system, and also as the input function of artery. The residual function is calculated from the following equation: Rtotal(t)=?iF (i) R(t-i) MTT= § R(t) dt (integral of the residual function) The concentration of the tracer at any time is given by : CT(t) = F § Cin (t’) R(t-t’) dt Deconvolution process is then used to solve for the R(t) and F. The volume of blood (BV) is then obtained using equation, BF = BV?MTT .These concepts can be applied on perfusion imaging of the brain. In such exercise, the middle cerebral artery (MCA) feeds blood to the brain tissue and it is considered as a single input source. The signal at a voxel positioned in the MCA is then measured to get the function of concentration input Cin(t) or the concentration curve within the slice at other voxels. The aforementioned calculation steps are then used to calculate the values of CBF using the data from Cin(t) and CT(t). It is worth noting that recirculation of risk during the acquisition of concentration time curve of the first bolus passage can occur and measures of combating such situations should be put in place. Note that the perfusion of tracers depend on the arterial inflow of each voxel, therefore, perfusion is regarded as a relative and not an absolute. The general assumption for this system is that what flows in is what flows out, meaning that the vascular system is a replicate of a linear system which has a single input and output and thus the system holds on for the theory of tracer kinetics (Hoa, 2009). Endogenous Tracers Exogenous tracers used in PWI are exemplified by using water in the blood as a tracer. This method depends on the protonation of water by inversion immediately at the point where large vessels are fed. After a given duration of delay, the target capillaries are reached by the protons in slice after which the protons diffuse into the water contained in the tissues. Normally acquired images have a different magnetisation to those resulting from the prepared protons, thus this technique is based on the acquisition of two different images. When comparing the normal images with the images prepared by protonation, the signal of inflowing blood in the target slices in the arteries is isolated. The realized signal difference due to the isolation is proportional to the amount of blood which entered the slice at the time of delay. This endogenous PWI method is known as either arterial spin tag or labeling (AST and ASL respectively). ASL or AST can be approached using the following outlined techniques: CASL (continuous arterial spin labeling) and PASL (Pulse arterial spin labeling) just to mention A few (Petrella & Provenzale, 2000). CASL can be achieved by either flow driven adiabatic inversion or pseudo-continuous saturation. The resultant effect of adiabatic inversion is doubled signal change. Just to highlight sequence of events in this technique: tissue magnetization due to continual labeling upstream stabilizes the tissue, multi-slice imaging using can be obtained using one or two rf coils, sensitivity to motion and transit time is reduced. CASL is of nuisance at high magnetic fields where levels of SAR are increased (Yonas, 2005). PASL: This technique depends on the labeling of an enormous blood volume at points where feeding of arteries takes place. The labeled volume flows into target slice during the period of inversion. Multiple slices with different flow contrast as result of discords in the blood transit time can be obtained. Tracer Kinetics Kinetic analysis for the aforementioned kinetic analysis model of exogenous tracers can be applied for the endogenous tracers. However, with regards to the magnetization difference resulting from the labeled blood flow, the following relationship is utilized: ?M = 2MbF?toC(t)R(t)m(t)dt where R(t) = R(t-t1) is the residual function, m(t) = m(t-t1) is the decay with regards to relaxation of T1 ,?M is the magnetization difference which is directly proportional to Mb the blood magnetization. C(t) is the normalized arterial concentration at voxel for the arriving magnetization and the sign ? is the integration with respect to t. The difference between T1 of the blood and tissue is negligible and therefore, the general equations for tagging when t is at rest and when t is continuous are, ?M = 2M х F х e-t/T1 and ?M = 2M х F хT1 respectively.(Bochar, 2001). The following assumptions holds for the ASL or AST 1. Complete exchange takes place between the tissue spins and labeled blood. This might not be the case for a very high flow such as that experienced by animals. 2. Measurements of ASL depend on transit times. The transit time varies for every tissue and underestimation of perfusion is a subject of long time. For instance, the brain’s grey matter has shorter transit time than the white matter, and it depends on the choice of imaging parameter. 3. Local relaxation properties are constant. However this might not be the case owing to the fact that unknown errors can occur. This is exemplified by a case where T2 remains unaffected by exchange in the tissue while the properties of arterial blood at T1 do not rely on size of vessel and oxygenation. Differences and similarities between the exogenous tracers and endogenous tracers Similarities They both employ similar approach to the trace kinetics which only differs at a stage due to magnetization difference experienced in ASL and not in exogenous. Both the methods have same limited volume coverage, reduced spatial resolution, and low signal to noise ratio (SNR). The low SNR in ASL is attributed to low spin percentage which leads to the signal perfusion (less than 1%) and can be improved averaging the signal with an aim of increasing the resultant scanning time. On the other hand high SNR of exogenous tracers is attributed to the presence of exogenous elements. Also, both the techniques depend on high temporal resolution which can be achieved by employing imaging techniques and if the high temporal resolution is availed, the result is high accuracy in estimation of haemodynamic parameters. Differences 1. In exogenous technique gadolinium remains intravascular when the blood-brain barrier is intact, while in the ASL the magnetic labelling of water molecules in the blood plasma makes it permeable and thus the protonated water diffuse relatively freely into the tissue and eventually through tissues neighbouring the target organ 2. Unlike exogenous technique, in ASL can lead to severe loss of brain signals. The estimated brain loss is 60%, and it is attributed to free proton transfer and trnsit time arrors experienced in ASL (Luypaert et al., 2001). 3. In exogenous technique, the tracer commonly used is gadolinium (Gd-DTPA) while in ASL; the mainly used tracer is water which is eventually protonated in the process. 4. In exogenous technique, signal delay is subject to T1 and T2 relaxations while in ASL the delay is attributed to T1 only 5. In exogenous technique, the signal intensity is directly proportional to the concentration of contrast inside the tissue while in the ASL; the signal intensity is proportional to the amount of magnetized blood taken in by the slice (Crawley et al., 2003). 6. There is an increased sensitivity to motion artefacts experienced by the ASL technique while sensitivity to motion decreases in the case of exogenous tracers. Clinical significance/applications of perfusion MRI Clinical applications range from diagnosis of stroke, cyst, tumours, angiogenesis, and other applications such as tumour staging, renal perfusion, cardiac imaging, myocardial perfusion, neurodegenerative and fMRI all of which are pathological. However, in most cases and if good results are to be obtained the techniques of DWI (Diffusion weighted imaging) and PWI are used in conjunction. 1. Stroke: Stroke maybe defined as inhibition or stoppage of blood flow to the brain leading to a quick halt of brain function(s). In Australia for example, this pathological condition is responsible for about 63,500 effects registered as deaths and disability cases. Its diagnosis requires the usage of both the DWI and PWI. DWI has the capability of identifying lesions, superior contrast, and identification of acute ischaemic lesions occurring in patients with numerous chronic lesions, all of which might not be identified by PWI. Procedurally, a lesion invisible on standard T2 (PWI) within first 24 hours maybe identified using MR angiography which shows the occlusion regions. Acute conditions refers to increased brain’s water content and loss of grey-white matter difference as revealed by proton DWIs or increase in T2 signal. This is an indication of tumour on the white matter and infarcts on both white and grey matter. Persistence in T2 signal elevation shows an increase in ADC values above normal values as the ischaemic tissue apparent diffusion coefficient remains low not less than 5-10 days. This ADC increase is attributed to necrosis and it varies with the presence, age and extent of the ischaemic event. Assessment of treatment requires the combination of both the PWI and DWI information especially in isolating thrombolytic therapy potent candidates. The following image shows the treatment of stroke: In the above diagram, images a, b, and c were obtained before treatment using DWI, MRA and MTT respectively while images d, e, and f were obtained after treatment using DWI, MRA, and MTT techniques respectively. 2. Cyst: This is an atypical closed sac like structure which may contain liquid,semi solid or gaseous matter, and may occur in place of the body within a tissue.Most cysts are visible on T1 and T2 weighted images owing to their liquid nature but some whose paramagnetic protein content is high shows shorter values than those expected from a liquid. However, complicated cystic lesions shows a queer solid tumour appearance on T1 and T2 images of weighted MR.A DWI technique shows the liquid nature of cysts indicated by a decrease in signal while a PWI technique shows a cyst devoid of blood floww hich is indicated by an increase in ADC with no blood flow. 3.Tumour area and angiogenesis: Using PWI, a tuomour maybe evident as a result of enhancing an area of image after contrast on standard images. This area does not coincide with the outer edge of the tumour.Blood mapping is done to differentiate tumour from necrosis and perfusion is the confirmatory test. For example, perfusion is low in a tissue damaged by radiation than in a reoccuring tumour. Types of tumours commonly identified using a correlation between tumour stage and ADCs are gliomas,astrocytic, and meningiomas. Angiogenesis refers to the emergence of new blood vessels in the tumour and such a tumour can survive and grow. This condition results in elevation of vasculature in tumours and perfusion si the best technique for identifying such malignant tumours or angiogenesis. The most utilzed haemodynamic parameter is the blood volume because it shows regions of greatest tumour activity as well as aiding in choosing the site for biopsy. 4. Tumour staging: This utilizes the blood volume. The most active lesions ahows increased blood volume and are heterogenous while the low grade tumours are characterised by low signal and homegenous blood volume maps. The blood volume is prefered because it shows regions of greatest tumour activity as well as aiding in choosing the site for biopsy.Exogenous tracewrs such as Gd-DTPA are moer utilized because they show the presence of a disturbed blood brain inhibitor which can be achieved by contrast enhancements. Additionally, the exodgenous tracers have the blood flow and blood volume information. ASl or endogenous tracers on the other hand have limited significance to tumour staging since they can only provide measures of blod flow and also, they do not provide the full coverage of the brain. 5.Renal perfusion: Analyses of renal perfusion are done assay the functionality. For example, ischaemic conditions shows a decrease in perfusion while microvascular diseases and inflamation indicates a scarring perfusion.Although Mr angiogarphy can detect renal aretery stenosis which can cause hypertension, it still requires PWI to establish bthe content of impairement of the function. Kidney cases show a number of difficulties using MR angiography, for example the exogenous tracers used in analyses assumes that the tracer is fully intravascular which might not be the case for the kidney especially the glomeruli filtrates. ASL on the other hand can be successfully used but it also posses difficulties such as transit time delays which cause increased errors attributed to the low flow in stenosed kidneys. 6. Cardiac imaging: Cardiac abnormalities are known for numerous death. PWI for cardiac is mostly done using exogenous tracers.In this technique, acquisition of multisliced images is made as soon as the injection of contrast has taken place after which the first contrast is let to pass and then assayed dynamically.More images might be taken after 5 minutes from the injection time done to capture improvement in the affected areas.Also, hindered improvement in infarcts visualizes the the size and extent of the effect and might only be seen 1-2 weeks old infarcts. 7. Myocardial perfusion: Myocardial perfusion is m jorly done to determine whether a n infarct is consistent in the myocardial wall or whether a live tissue is endo-infarct or epi-infarct. Normally, the perfusion analyses showa the shortening effect of T1 from the paramagnetiic tracer (Gd-DTPA) which results in the signal intensity increase of the weighted image of T1 while hypofused myocardium shows lack of signal intensity. All this are indications of ischaemic of fibrotiuc region which are further analysed by perfusion. 8. Neurodegeneretaive Diseases: These are the diseases which destroys or degrades the nervous system and are examplified by Alzheimer’s disease and Pick’s domentia which occurs in the brain. The mostly used parameter for diagnosis of such conditions is blood volume. Any change in the cerebral blood volume is an indication of neural loss and reflect synapses. A decreased rCBV and rCBF is in the Alzheimer condition is an indication of temporal and parietal cortices and its symptoms are memory loss, apraxia, impaired visuospatial perception, aphasia, and personality changes. Picks’s domentia is the result of progressive Alzheimer’s disease. 9.Functional MRI (fMRI): This is done to assay the localised variations in the blood volume, blood flow, metabolism, and oxygen content of the cerebral activation. fMRI is essential in psychological examinations of the brain’s functions and in the event of acquiring information necessary for therapeutic or surgical process. Exogenous tracers (gadolinium) which requires repeated injection of contrast agent as a bolus might be comonly used, but owing to its insidious nature, they are not preferably used in fMRI and instead ASL is prefered to them. ASL perceives task-related variations in rCBF (regional cerebral blood flow). Increases in local blood flow are linked to neural activity which are dramatic and strong in the visual cortices, somatosensory and primary motor.fMRI benefits include the provision of a more sensitive spatial localisation of the target interest. However, it is disadvantegeous in that it requires EPI methods to show the BOLD (Blood oxygen level dependent) contrasts owing to the fact that EPI have more superior temporal resolution than ASL and that ASL provides a more challenging technique in comparing the BOLD.( Crawley, A 2003 and the MRES707 module 5& 6) References Bochar, S. (2001). Diffusion and perfusion weighted magnetic resonance imaging of acute ischemic stroke. Supplement to Applied Radiology, 30 (4), 38-44. Crawley, A., Poublanc, J., Ferrari, P., & Roberts, T. (2003) Basics of diffusion and perfusion MRI. Applied Radiology, 13-23. Hoa, D. (2009). Cerebral perfusion MRI. Retrieved from http://www.imaios.com/en/e-Courses/e-MRI/Cerebral-perfusion-imaging. Lorenz, C. (2004). Automated perfusion-weighted MRI metrics via localized arterial input functions (pp. 1-70). Department of Engineering and Computer Science, Massachusetts Institute of Technology. Luypaert, R., Boujraf, S., Sourbron, S., & Osteaux, M. (2001) Diffusion and perfusion MRI: Basic physics. European Journal of Radiology, 38, 19-27. Yonas, H. (2005). Comparative overview of brain of brain perfusion imaging techniques. Petrella, J., & Provenzale, J. (2000). MR perfusion of the brain: Techniques and applications. American Journal of Roentology, 175 (1), 207-219. Thomas, D., Oridge, R., & Taylor, A. (2009). Development of arterial spin labeling MRI method for mapping cerebral perfusion in the human brain. MRI methods development. UCL department of medical physics and bioengineering. Retrieved from http://www.ucl.ac.uk/medphys/research/mri/methods_development Read More