Assessment of synaptic loss in mouse models of ß-amyloid and tau pathology using [18F]UCB-H PET imaging.

OBJECTIVE: In preclinical research, the use of [18F]Fluorodesoxyglucose (FDG) as a biomarker for neurodegeneration may induce bias due to enhanced glucose uptake by immune cells. In this study, we sought to investigate synaptic vesicle glycoprotein 2A (SV2A) PET with [18F]UCB-H as an alternative preclinical biomarker for neurodegenerative processes in two mouse models representing the pathological hallmarks of Alzheimer's disease (AD). METHODS: A total of 29 PS2APP, 20 P301S and 12 wild-type mice aged 4.4 to 19.8 months received a dynamic [18F]UCB-H SV2A-PET scan (14.7 ± 1.5 MBq) 0-60 min post injection. Quantification of tracer uptake in cortical, cerebellar and brainstem target regions was implemented by calculating relative volumes of distribution (VT) from an image-derived-input-function (IDIF). [18F]UCB-H binding was compared across all target regions between transgenic and wild-type mice. Additional static scans were performed in a subset of mice to compare [18F]FDG and [18F]GE180 (18 kDa translocator protein tracer as a surrogate for microglial activation) standardized uptake values (SUV) with [18F]UCB-H binding at different ages. Following the final scan, a subset of mouse brains was immunohistochemically stained with synaptic markers for gold standard validation of the PET results. RESULTS: [18F]UCB-H binding in all target regions was significantly reduced in 8-months old P301S transgenic mice when compared to wild-type controls (temporal lobe: p = 0.014; cerebellum: p = 0.0018; brainstem: p = 0.0014). Significantly lower SV2A tracer uptake was also observed in 13-months (temporal lobe: p = 0.0080; cerebellum: p = 0.006) and 19-months old (temporal lobe: p = 0.0042; cerebellum: p = 0.011) PS2APP transgenic versus wild-type mice, whereas the brainstem revealed no significantly altered [18F]UCB-H binding. Immunohistochemical analyses of post-mortem mouse brain tissue confirmed the SV2A PET findings. Correlational analyses of [18F]UCB-H and [18F]FDG using Pearson's correlation coefficient revealed a significant negative association in the PS2APP mouse model (R = -0.26, p = 0.018). Exploratory analyses further stressed microglial activation as a potential reason for this inverse relationship, since [18F]FDG and [18F]GE180 quantification were positively correlated in this cohort (R = 0.36, p = 0.0076). CONCLUSION: [18F]UCB-H reliably depicts progressive synaptic loss in PS2APP and P301S transgenic mice, potentially qualifying as a more reliable alternative to [18F]FDG as a biomarker for assessment of neurodegeneration in preclinical research.

MR-compatibility assessment of MADPET4: a study of interferences between an SiPM-based PET insert and a 7 T MRI system.

Compromises in the design of a positron emission tomography (PET) insert for a magnetic resonance imaging (MRI) system should minimize the deterioration of image quality in both modalities, particularly when simultaneous demanding acquisitions are performed. In this work, the advantages of using individually read-out crystals with high-gain silicon photomultipliers (SiPMs) were studied with a small animal PET insert for a 7 T MRI system, in which the SiPM charge was transferred to outside the MRI scanner using coaxial cables. The interferences between the two systems were studied with three radio-frequency (RF) coil configurations. The effects of PET on the static magnetic field, flip angle distribution, RF noise, and image quality of various MRI sequences (gradient echo, spin echo, and echo planar imaging (EPI) at 1H frequency, and chemical shift imaging at 13C frequency) were investigated. The effects of fast-switching gradient fields and RF pulses on PET count rate were studied, while the PET insert and the readout electronics were not shielded. Operating the insert inside a 1H volume coil, used for RF transmission and reception, limited the MRI to T1-weighted imaging, due to coil detuning and RF attenuation, and resulted in significant PET count loss. Using a surface receive coil allowed all tested MR sequences to be used with the insert, with 45-59% signal-to-noise ratio (SNR) degradation, compared to without PET. With a 1H/13C volume coil inside the insert and shielded by a copper tube, the SNR degradation was limited to 23-30% with all tested sequences. The insert did not introduce any discernible distortions into images of two tested EPI sequences. Use of truncated sinc shaped RF excitation pulses and gradient field switching had negligible effects on PET count rate. However, PET count rate was substantially affected by high-power RF block pulses and temperature variations due to high gradient duty cycles.

Enhancing spatial resolution of (18)F positron imaging with the Timepix detector by classification of primary fired pixels using support vector machine.

Position-sensitive positron cameras using silicon pixel detectors have been applied for some preclinical and intraoperative clinical applications. However, the spatial resolution of a positron camera is limited by positron multiple scattering in the detector. An incident positron may fire a number of successive pixels on the imaging plane. It is still impossible to capture the primary fired pixel along a particle trajectory by hardware or to perceive the pixel firing sequence by direct observation. Here, we propose a novel data-driven method to improve the spatial resolution by classifying the primary pixels within the detector using support vector machine. A classification model is constructed by learning the features of positron trajectories based on Monte-Carlo simulations using Geant4. Topological and energy features of pixels fired by (18)F positrons were considered for the training and classification. After applying the classification model on measurements, the primary fired pixels of the positron tracks in the silicon detector were estimated. The method was tested and assessed for [(18)F]FDG imaging of an absorbing edge protocol and a leaf sample. The proposed method improved the spatial resolution from 154.6 ± 4.2 µm (energy weighted centroid approximation) to 132.3 ± 3.5 µm in the absorbing edge measurements. For the positron imaging of a leaf sample, the proposed method achieved lower root mean square error relative to phosphor plate imaging, and higher similarity with the reference optical image. The improvements of the preliminary results support further investigation of the proposed algorithm for the enhancement of positron imaging in clinical and preclinical applications.

Detection models for freehand SPECT reconstruction.

Nuclear imaging modalities are commonly used tools in today's diagnostics and therapy planning. However for interventional use they suffer from drawbacks which limit their application. Freehand SPECT was developed to provide 3D functional imaging during interventions. It combines a nuclear detector with an optical tracking system to obtain its position and orientation in space and synchronizes this with the detector readings. This information can be used to compute a 3D tomographic reconstruction of an activity distribution of a nuclear tracer. As there is no fixed geometry, the system matrix has to be computed on the fly. This is done with models of the detection process for completely arbitrary freehand acquisitions. The accuracy of the reconstructions is highly dependent on the used models of the detection process. Different models of the detection process were developed and evaluated in this work, in particular two analytical models as well as lookup tables generated from either real measurements or Monte Carlo simulations. We showed that it is possible to perform acceptable reconstructions with a simple but efficient analytical model. The use of lookup tables to generate the system matrix in Freehand SPECT is a fast solution with good accuracy.

Textural Parameters of Tumor Heterogeneity in ¹8F-FDG PET/CT for Therapy Response Assessment and Prognosis in Patients with Locally Advanced Rectal Cancer.

UNLABELLED: (18)F-FDG PET/CT is effective in the assessment of therapy response. Changes in glucose uptake or tumor size are used as a measure. Tumor heterogeneity was found to be a promising predictive and prognostic factor. We investigated textural parameters for their predictive and prognostic capability in patients with rectal cancer using histopathology as the gold standard. In addition, a comparison to clinical outcome was performed. METHODS: Twenty-seven patients with rectal cancer underwent (18)F-FDG PET/CT before, 2 wk after the start, and 4 wk after the completion of neoadjuvant chemoradiotherapy. In all PET/CT scans, conventional parameters (tumor volume, diameter, maximum and mean standardized uptake values, and total lesion glycolysis [TLG]) and textural parameters (coefficient of variation [COV], skewness, and kurtosis) were determined to assess tumor heterogeneity. Values on pretherapeutic PET/CT as well as changes early in the course of therapy and after therapy were compared with histopathologic response. In addition, the prognostic value was assessed by correlation with time to progression and survival time. RESULTS: The COV showed a statistically significant capability to assess histopathologic response early in therapy (sensitivity, 68%; specificity, 88%) and after therapy (79% and 88%, respectively). Thereby, the COV had a higher area under the curve in receiver-operating-characteristic analysis than did any analyzed conventional parameter for early and late response assessment. The COV showed a statistically significant capability to evaluate disease progression and to predict survival, although the latter was not statistically significant. CONCLUSION: Tumor heterogeneity assessed by the COV, being superior to the investigated conventional parameters, is an important predictive factor in patients with rectal cancer. Furthermore, it can provide prognostic information. Therefore, its application is an important step for personalized treatment of rectal cancer.

Quantitative assessment of hypoxia kinetic models by a cross-study of dynamic 18F-FAZA and 15O-H2O in patients with head and neck tumors.

UNLABELLED: Several kinetic models have been proposed to assess the underlying oxygenation status behind hypoxia tracer uptake and have shown advantages, compared with static analysis, in discriminating hypoxic regions. However, the quantitative assessment of mathematic models that take into consideration clinical applications and their biologic nature is still challenging. We performed a feasibility study to assess hypoxia kinetic models using voxelwise cross-analysis between the uptake of the perfusion tracer (15)O-H(2)O and the hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA). METHODS: Five patients with advanced head and neck cancer were included. For each patient, dynamic sequences of (15)O-H(2)O for 5 min and (18)F-FAZA for 60 min were acquired consecutively after injections of approximately 1 GBq and 300 MBq of each tracer, respectively. The compartment model, Thorwarth model, Patlak plot, Logan plot, and Cho model were applied to model the process of tracer transport and accumulation under hypoxic conditions. The standard 1-tissue-compartment model was used to compute a perfusion map for each patient. The hypoxia kinetic models were based on the assumption of a positive correlation between tracer delivery and perfusion and a negative (inverse) correlation between tracer accumulation (hypoxia) and perfusion. RESULTS: Positive correlations between tracer delivery and perfusion were observed for the Thorwarth and Cho models in all patients and for the reversible and irreversible 2-compartment models in 4 patients. Negative correlations between tracer accumulation and perfusion were observed for the reversible 2-compartment model in all patients and for the irreversible 2-compartment model and Cho model in 4 patients. When applied to normal skeletal muscle, the smallest correlation variance over all 5 patients was observed for the reversible 2-compartment model. CONCLUSION: Hypoxia kinetic modeling delivers different information from static measurements. Different models generate different results for the same patient, and they even can lead to opposite physiologic interpretations. On the basis of our assessment of physiologic precision and robustness, the reversible 2-compartment model corresponds better to the expectations of our assumptions than the other investigated models.

[11C]Choline as pharmacodynamic marker for therapy response assessment in a prostate cancer xenograft model.

PURPOSE: [(11)C]Choline has been established as a PET tracer for imaging prostate cancer. The aim of this study was to determine whether [(11)C]choline can be used for monitoring the effects of therapy in a prostate cancer mouse xenograft model. METHODS: The androgen-independent human prostate cancer cell line PC-3 was implanted subcutaneously into the flanks of 13 NMRI (nu/nu) mice. All mice were injected 4-6 weeks after xenograft implantation with 37 MBq [(11)C]choline via a tail vein. Dynamic imaging was performed for 60 min with a small-animal PET/CT scanner (Siemens Medical Solutions). Six mice were subsequently injected intravenously with docetaxel twice (days 1 and 5) at a dose of 3 mg/kg body weight. Seven mice were treated with PBS as a control. [(11)C]Choline imaging was performed prior to and 1, 2 and 3 weeks after treatment. To determine choline uptake the images were analysed in terms of tumour-to-muscle (T/M) ratios. Every week the size of the implanted tumour was determined with a sliding calliper. RESULTS: The PC-3 tumours could be visualized by [(11)C]choline PET. Before treatment the T/M(mean) ratio was 1.6+/-0.5 in the control group and 1.8+/-0.4 in the docetaxel-treated group (p=0.65). There was a reduction in the mean [(11)C]choline uptake after docetaxel treatment as early as 1 week after initiation of therapy (T/M ratio 1.8+/-0.4 before treatment, 0.9+/-0.3 after 1 week, 1.1+/-0.3 after 2 weeks and 0.8+/-0.2 after 3 weeks). There were no decrease in [(11)C]choline uptake in the control group following treatment (T/M ratio 1.6+/-0.5 before treatment, 1.7+/-0.4 after 1 week, 1.8+/-0.7 after 2 weeks and 1.7+/-0.4 after 3 weeks). For analysis of the dynamic data, a generalized estimation equation model revealed a significant decrease in the T/M(dyn) ratios 1 week after docetaxel treatment, and the ratio remained at that level through week 3 (mean change -0.93+/-0.24, p<0.001, after 1 week; -0.78+/-0.21, p<0.001, after 2 weeks; -1.08+/-0.26, p<0.001, after 3 weeks). In the control group there was no significant decrease in the T/M(dyn) ratios (mean change 0.085+/-0.39, p=0.83, after 1 week; 0.31+/-0.48, p=0.52, after 2 weeks; 0.11+/-0.30, p=0.72, after 3 weeks). Metabolic changes occurred 1 week after therapy and preceded morphological changes of tumour size during therapy. CONCLUSION: Our results demonstrate that [(11)C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer.

Monte Carlo simulations of the count rate performance of a clinical whole-body MR/PET scanner.

The combination of MR and PET scanners can provide a powerful tool for clinical diagnosis and investigation. Among the existing approaches, the most challenging is that of complete hardware integration of both scanners. Such an integrated tomograph would allow simultaneous acquisition of both modalities, which could help solve issues such as cardiac and respiratory motion. Full integration imposes restrictions on the design of the PET part, such as detector configuration and maximum ring diameter. Furthermore, MR components surrounding the PET detector ring may cause gamma ray interactions, thus affecting PET performance. The purpose of this article is to assess the performance of a hypothetical whole-body integrated MR/PET scanner using Monte Carlo simulation techniques and compare it to state-of-the-art PET/CT devices used in clinical routine. The Monte Carlo simulation toolkit used for this study is the GEANT4 application for emission tomography. A hypothetical whole-body MR/PET tomograph fully integrated at hardware level and positioned between gradient and local coils of the MR scanner has been modeled. The NEMA 2-2001 protocol has been used to configure the simulations in order to measure sensitivity, scatter fraction, count losses, and random detections. Global sensitivity values as a function of the lower-level discriminator (LLD) energy are provided for time resolutions of 5 and 2.25 ns. In addition, the scatter fraction of the system is studied as a function of the LLD for energy resolution values of 10%, 15%, and 20%. Finally, true, scatter, random, and noise equivalent count rate curves as a function of activity concentration are given for dead-time values of 136, 432, and 1150 ns and for time resolution values of 2.25 and 5 ns. The influence on the count rate performance of the integrated PET scanner of the new geometry and interfering MR elements has been measured. The results show that the interference of the MR components has a much lower impact than the reduction in the detector ring diameter. Due to the larger solid angle coverage, the sensitivity is higher than that measured for a clinical PET/CT system (6200-10 900 cps/MBq at the center of the scanner) but not enough to compensate the degradation of the noise equivalent count rate due to increased scatter detection. The simulations prove the viability of an integrated MR/PET system and suggest that priority has to be given to either the improvement of the temporal resolution or the correction of triple coincidences if competitive performance is to be achieved.

Assessment of tumor volumes in skull base glomus tumors using Gluc-Lys[(18)F]-TOCA positron emission tomography.

PURPOSE: To assess a threshold for Gluc-Lys[(18)F]-TOCA positron emission tomography (PET) in target volume delineation of glomus tumors in the skull base and to compare with MRI-based target volume delineation. METHODS AND MATERIALS: The threshold for volume segmentation in the PET images was determined by a phantom study. Nine patients with a total of 11 glomus tumors underwent PET either with Gluc-Lys[(18)F]-TOCA or with (68)Ga-DOTATOC (in 1 case). All patients were additionally scanned by MRI. Positron emission tomography and MR images were transferred to a treatment-planning system; MR images were analyzed for lesion volume by two observers, and PET images were analyzed by a semiautomated thresholding algorithm. RESULTS: Our phantom study revealed that 32% of the maximum standardized uptake value is an appropriate threshold for tumor segmentation in PET-based target volume delineation of gross tumors. Target volume delineation by MRI was characterized by high interobserver variability. In contrast, interobserver variability was minimal if fused PET/MRI images were used. The gross tumor volumes (GTVs) determined by PET (GTV-PET) showed a statistically significant correlation with the GTVs determined by MRI (GTV-MRI) in primary tumors; in recurrent tumors higher differences were found. The mean GTV-MRI was significantly higher than mean GTV-PET. The increase added by MRI to the common volume was due to scar tissue with strong signal enhancement on MRI. CONCLUSIONS: In patients with glomus tumors, Gluc-Lys[(18)F]-TOCA PET helps to reduce interobserver variability if an appropriate threshold for tumor segmentation has been determined for institutional conditions. Especially in patients with recurrent tumors after surgery, Gluc-Lys[(18)F]-TOCA PET improves the accuracy of GTV delineation.