TOWARDS THE MONITORING OF CARDIAC STEM CELL THERAPY USING SPECT/CT

My thesis explores several technical challenges associated with the use of SPECT/CT in monitoring cardiac regenerative therapy. This first aspect concerns the adoption of solid-state gamma cameras, which is inevitable if their costs continue to decrease.

Since stem cells are sensitive to radiation dose, it is desirable to label them with as little radioisotope as possible. Our group has performed studies to determine the toxicity levels acceptable for cells to continue to proliferate, which was shown to be 0.1 Bq of 111In per cell, for the case of bone marrow derived mesenchymal stem cells [25]. In our studies involving canine models of heart disease, we would aim to transplant approximately 30 million cells [64]. Thus, at most, the activity transplanted to a target site (such as an infarction) would be 3 MBq. This activity level is much lower than the 20 to 30MBq of 111In used to label white blood cells in routine clinical applications. In addition, these cells are widely dispersed throughout the whole body, as opposed to the limited geographic distribution of the transplanted stem cells. With such a limited amount of radioactivity, greater attention must be paid to maximizing image quality including the implementation of corrections for the physical effects of gamma ray attenuation and scatter. One opportunity for minimizing the presence of scatter in SPECT may lie with the adoption of solid-state gamma cameras. Compared with conventional gammas cameras utilizing scintillation crystals and photomultiplier tubes, solid-state detectors can achieve superior energy and spatial resolution, in addition to enhanced image contrast [56]– all of which would benefit imaging transplanted radiolabeled cells. The use of solid-state gamma cameras is currently limited due to very high manufacturing costs, especially for large field-of-view (FOV) detectors. For the application of monitoring cardiac stem cell therapy, however, a large FOV detector may not be necessary since the region of interest – the heart – is relatively small. However, in general, the use of small detectors requires caution since object truncation always becomes more of a concern [65, 66]. However no one has addressed the problems of

image truncation when performing hot-spot imaging. It will be shown that provided the hot-spot is within each projection that truncation is less of a problem if the reconstruction method is guided by an anatomical imaging method such as CT.

When imaging radioactive distributions larger than the gamma camera, artifacts caused by object truncation can appear at the periphery of the FOV. These artifacts can be especially prominent in iterative reconstructions, and are the result of the reconstruction algorithm attempting to find a distribution of activity in that FOV most consistent with the projection data (as described in Section 1.4 earlier). However, since there is by definition, radioactivity beyond the FOV, the algorithm converges to an incorrect solution; and the error is seen as the “hot rim” truncation artifact.

Correcting for truncation artifacts is important when imaging a small FOV because the artifact can easily interfere with the imaging of the object of interest. Methods for correcting image truncation have been discussed in the past [66, 67]. In CHAPTER 4, I evaluate an iterative reconstruction algorithm modified to reduce the presence of truncation artifacts. The algorithm is evaluated in the context of cardiac imaging where the imaging apparatus is a small FOV gamma camera coupled to a large FOV X-ray CT.

The low amount of activity used in cardiac stem cell therapy monitoring using SPECT emphasizes the need for dealing with the physical effects of scatter and attenuation. The previous section introduced the necessity for improved scatter rejection; however, the matter of gamma-ray attenuation will also need to be addressed. Currently the most widely implemented method for attenuation correction is via X-ray CT. However, as previously described, two CT designs exist for SPECT/CT systems; a slow-

rotation CT and a fast-rotation CT. We should note a third CT design exists that incorporates a flat panel x-ray detector that can image the entire chest in a single rotation. At the time of the experiments the flat panel design was not available and therefore the latter two were studied. Experiments were required to determine which design will perform a more correct method of attenuation correction. In Chapter 2, I study how respiratory motion impacts the quality of cardiac SPECT imaging when attenuation correction is based on fast vs slow rotation CT. I evaluate both designs using computer simulations and experiments in a canine model.

Many aspects of cardiac stem cell therapy remain to be studied and optimized. To achieve successful cell therapy, it is believed that cells should be transplanted into the periphery of the infarct, and not directly in the infarct center where blood flow is compromised [68]. Therefore, methods to properly localize transplanted cells in relation to blood flow must be developed. Here, SPECT can offer a solution due to its multi- spectral imaging capabilities. We previously demonstrated the ability of SPECT to image simultaneously, in a canine model, cardiac-transplanted 111In-labeled cells, myocardial perfusion using 99mTc-MIBI, and an 131I-labeled FIAU reporter probe (See Figure 1.7). However, the resolution of the SPECT blood flow image with 99m_{Tc is not}

ideal to properly localize the cells relative to the region of reduced blood flow. CT has been shown to be a viable alternative for perfusion imaging [69, 70], and has the resolution required to localize the 111In labeled cells seen on SPECT. Recent studies have confirmed that the CT in hybrid systems such as PET/CT can be used for perfusion imaging [71]. In Chapter 3, I demonstrate a newly developed method of combining

SPECT with first-pass perfusion CT for the localization of cells in relation to region of reduced blood flow in a canine model of myocardial infarction.

Figure 1.7: Multi-spectral imaging using SPECT

SPECT is capable of imaging multiple isotopes simultaneously. In this particular example of a canine study, the injected cells were labeled with 111_{In (GREEN), the}

cardiac perfusion image was obtained with 99mTc (RED), and a reporter probe imaged with 131I (BLUE). All of these isotopes are combined to form a single image.