Reproducible Analysis of Rat Brain PET Studies Using an Additional [(18)F]NaF Scan and an MR-Based ROI Template

Background. An important step in the analysis of positron emission tomography (PET) studies of the brain is the definition of regions of interest (ROI). Image coregistration, ROI analysis, and quantification of brain PET data in small animals can be observer dependent. The purpose of this study was to investigate the feasibility of ROI analysis based on a standard MR template and an additional [(18)F]NaF scan. Methods. [(18)F]NaF scans of 10 Wistar rats were coregistered with a standard MR template by 3 observers and derived transformation matrices were applied to corresponding [(11)C]AF150(S) images. Uptake measures were derived for several brain regions delineated using the MR template. Overall agreement between the 3 observers was assessed by interclass correlation coefficients (ICC) of uptake data. In addition, [(11)C]AF150(S) ROI data were compared with ex vivo biodistribution data. Results. For all brain regions, ICC analysis showed excellent agreement between observers. Reproducibility, estimated by calculation of standard deviation of the between-observer differences, was demonstrated by an average of 17% expressed as coefficient of variation. Uptake of [(11)C]AF150(S) derived from ROI analysis closely matched ex vivo biodistribution data. Conclusions. The proposed method provides a reproducible and tracer-independent method for ROI analysis of rat brain PET data

Advanced brain dopamine transporter imaging in mice using small-animal SPECT/CT

Abstract. The stable marriage problem has recently been studied in its general setting, where both ties and incomplete lists are allowed. It is NP-hard to find a stable matching of maximum size, while any stable matching is a maximal matching and thus trivially a factor two approximation. In this paper, we give the first nontrivial result for approximation of factor less than two. Our algorithm achieves an approximation ratio of 2/(1+L −2) for instances in which only men have ties of length at most L. When both men and women are allowed to have ties, we show a ratio of 13/7(< 1.858) for the case when ties are of length two. We also improve the lower bound on the approximation ratio to 2

Targeting murine heart and brain: visualisation conditions for multi-pinhole SPECT with 99mTc- and 123I-labelled probes

The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of (123)I- and (99m)Tc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake.A Triad 88/Trionix system with three 6-pinhole collimators was used for investigation of dose requirements for imaging of the dopamine D(2) receptor ligand [(123)I]IBZM and the cerebral perfusion tracer [(99m)Tc]HMPAO (1.2-0.4 MBq/g body weight) in healthy mice. The fatty acid [(123)I]IPPA (0.94 +/- 0.05 MBq/g body weight) and the perfusion tracer [(99m)Tc]sestamibi (3.8 +/- 0.45 MBq/g body weight) were applied to cardiomyopathic mice overexpressing the prostaglandin EP(3) receptor.In vivo imaging and in vitro data revealed 45 kBq total cerebral uptake and 201 kBq cardiac uptake as thresholds for visualisation of striatal [(123)I]IBZM and of cardiac [(99m)Tc]sestamibi using 100 and 150 s acquisition time, respectively. Alterations of maximal cerebral uptake of [(123)I]IBZM by >20% (116 kBq) were verified with the prerequisite of 50% striatal of total uptake. The labelling with [(99m)Tc]sestamibi revealed a 30% lower uptake in cardiomyopathic hearts compared to wild types. [(123)I]IPPA uptake could be visualised at activity doses of 0.8 MBq/g body weight.Multi-pinhole SPECT enables detection of alterations of the cerebral uptake of (123)I- and (99m)Tc-labelled tracers in an appropriate dose range in murine models targeting physiological processes in brain and heart. The thresholds of detection for differences in the tracer uptake determined under the conditions of our experiments well reflect distinctions in molar activity and uptake characteristics of the tracers

Molecular Targeting of Carbonic Anhydrase IX in Mice with Hypoxic HT29 Colorectal Tumor Xenografts

Background: Carbonic anhydrase IX (CAIX) is a membrane spanning protein involved in the enzymatic regulation of tumor acid-base balance. CAIX has been shown to be elevated in a number of hypoxic tumor types. The purpose of this study was to determine the efficiency of intact and IgG fragments of cG250 to target CAIX in vivo in a hypoxic tumor model. Methodology/Principal Findings: Conventional biodistribution studies were performed with 111 In-DO3A-cG250, 111 In-DO3A-F(ab’)2-cG250 and 111 In-DO3A-Fab-cG250. Additional ex vivo analysis of the tumor was performed with markers for tumor hypoxia, blood perfusion and endogenous CAIX expression. All four data sets were digitally correlated to determine the optimal agent for determining hypoxia in a HT29 colon cancer xenograft. The HT29 human colorectal tumor xenografts show strong CAIX expression in hypoxic areas of poor blood perfusion. The intact IgG had an initial high focal uptake at the periphery of these hypoxic regions and penetration into the areas of highest CAIX expression over the 7-day study period. The lower molecular weight antibody fragments had a faster uptake into areas of high CAIX expression, but had a much lower absolute uptake at the optimal imaging times. Conclusions/Significance: For the clinical detection of hypoxia induced CAIX using cG250 antibody based agents, imagin

Validation of 3\u27-deoxy-3\u27-[18F]-fluorothymidine positron emission tomography for image-guidance in biologically adaptive radiotherapy

Accelerated tumor cell repopulation during radiation therapy is one of the leading causes for low survival rates of head-and-neck cancer patients. The therapeutic effectiveness of radiotherapy could be improved by selectively targeting proliferating tumor subvolumes with higher doses of radiation. Positron emission tomography (PET) imaging with 3´-deoxy-3´-[18F]-fluorothymidine (FLT) has shown great potential as a non-invasive approach to characterizing the proliferation status of tumors. This thesis focuses on histopathological validation of FLT PET imaging specifically for image-guidance applications in biologically adaptive radiotherapy. The lack of experimental data supporting the use of FLT PET imaging for radiotherapy guidance is addressed by developing a novel methodology for histopathological validation of PET imaging. Using this new approach, the spatial concordance between the intratumoral pattern of FLT uptake and the spatial distribution of cell proliferation is demonstrated in animal tumors. First, a two-dimensional analysis is conducted comparing the microscopic FLT uptake as imaged with autoradiography and the distribution of active cell proliferation markers imaged with immunofluorescent microscopy. It was observed that when tumors present a pattern of cell proliferation that is highly dispersed throughout the tumor, even high-resolution imaging modalities such as autoradiography could not accurately determine the extent and spatial distribution of proliferative tumor subvolumes. While microscopic spatial coincidence between high FLT uptake regions and actively proliferative subvolumes was demonstrated in tumors with highly compartmentalized/aggregated features of cell proliferation, there were no conclusive results across the entire set of utilized tumor specimens. This emphasized the need for addressing the limited resolution of FLT PET when imaging microscopic patterns of cell proliferation. This issue was emphasized in the second part of the thesis where the spatial concordance between volumes segmented on FLT simulated FLT PET images and the three dimensional spatial distribution of cell proliferation markers was analyzed

Automated analysis of small animal PET studies through deformable registration to an atlas

Purpose: This work aims to develop a methodology for automated atlas-guided analysis of small animal positron emission tomography (PET) data through deformable registration to an anatomical mouse model. Methods: A non-rigid registration technique is used to put into correspondence relevant anatomical regions of rodent CT images from combined PET/CT studies to corresponding CT images of the Digimouse anatomical mouse model. The latter provides a pre-segmented atlas consisting of 21 anatomical regions suitable for automated quantitative analysis. Image registration is performed using a package based on the Insight Toolkit allowing the implementation of various image registration algorithms. The optimal parameters obtained for deformable registration were applied to simulated and experimental mouse PET/CT studies. The accuracy of the image registration procedure was assessed by segmenting mouse CT images into seven regions: brain, lungs, heart, kidneys, bladder, skeleton and the rest of the body. This was accomplished prior to image registration using a semi-automated algorithm. Each mouse segmentation was transformed using the parameters obtained during CT to CT image registration. The resulting segmentation was compared with the original Digimouse atlas to quantify image registration accuracy using established metrics such as the Dice coefficient and Hausdorff distance. PET images were then transformed using the same technique and automated quantitative analysis of tracer uptake performed. Results: The Dice coefficient and Hausdorff distance show fair to excellent agreement and a mean registration mismatch distance of about 6mm. The results demonstrate good quantification accuracy in most of the regions, especially the brain, but not in the bladder, as expected. Normalized mean activity estimates were preserved between the reference and automated quantification techniques with relative errors below 10% in most of the organs considered. Conclusion: The proposed automated quantification technique is reliable, robust and suitable for fast quantification of preclinical PET data in large serial studie

In Vivo Imaging of Glial Activation after Unilateral Labyrinthectomy in the Rat: A [F-18]GE180-PET study

The functional relevance of reactive gliosis for recovery from acute unilateral vestibulopathy is unknown. In the present study, glial activation was visualized in vivo by [F-18]GE180-PET in a rat model of unilateral labyrinthectomy (UL) and compared to behavioral vestibular compensation (VC) overtime. 14 Sprague-Dawley rats underwent a UL by transtympanic injection of bupivacaine/arsenilate, 14 rats a SHAM UL (injection of normal saline). Glial activation was depicted with [F-18]GE180-PET and ex vivo autoradiography at baseline and 7, 15, 30 days after UL/SHAM UL. Postural asymmetry and nystagmus were registered at 1, 2, 3, 7, 15, 30 days after UL/SHAM UL. Signs of vestibular imbalance were found only after UL, which significantly decreased until days 15 and 30. In parallel, [F-18]GE180-PET and ex vivo autoradiography depicted glial activation in the ipsilesional vestibular nerve and nucleus on days 7 and 15 after UL. Correlation analysis revealed a strong negative association of [F-18]GE180 uptake in the ipsilesional vestibular nucleus on day 7 with the rate of postural recovery (R = -0.90, p < 0.001), suggesting that glial activation accelerates VC. In conclusion, glial activation takes place in the ipsilesional vestibular nerve and nucleus within the first 30 days after UL in the rat and can be visualized in vivo by [F-18]GE180-PET