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Excessive activation of inflammatory signaling pathways seems to be a hallmark of epileptogenesis. Positron emission tomography (PET) allows in vivo detection of brain inflammation with spatial information and opportunities for longitudinal follow-up scanning protocols. Here, we assessed whether molecular imaging of the 18 kDa translocator protein (TSPO) can serve as a biomarker for the development of epilepsy. Therefore, brain uptake of [ 18 F]GE-180, a highly selective radioligand of TSPO, was investigated in a longitudinal PET study in a chronic rat model of temporal lobe epilepsy. Analyses revealed that the influence of the epileptogenic insult on [ 18 F]GE-180 brain uptake was most pronounced in the earlier phase of epileptogenesis. Differences were evident in various brain regions during earlier phases of epileptogenesis with [ 18 F]GE-180 standardized uptake value enhanced by 2.1 to 2.7fold. In contrast, brain regions exhibiting differences seemed to be more restricted with less pronounced increases of tracer uptake by 1.8-2.5fold four weeks following status epilepticus and by 1.5-1.8fold in the chronic phase. Based on correlation analysis, we were able to identify regions with a predictive value showing a correlation with seizure development. These regions include the amygdala as well as a cluster of brain areas. This cluster comprises parts of different brain regions, e.g. the hippocampus, parietal cortex, thalamus, and somatosensory cortex. In conclusion, the data provide evidence that [ 18 F]GE-180 PET brain imaging can serve as a biomarker of epileptogenesis. The identification of brain regions with predictive value might facilitate the development of preventive concepts as well as the early assessment of the interventional success. Future studies are necessary to further confirm the predictivity of the approach.

Objectives: In recent years several [ 18 F]-labelled amyloid PET tracers have been developed and have obtained clinical approval. There is accumulating evidence that early (post injection) acquisitions with these tracers are equally informative as conventional blood flow and metabolism studies for diagnosis of Alzheimer's disease, but there have been few side-by-side studies. Therefore, we investigated the performance of early acquisitions of [ 18 F]-florbetaben (FBB) PET compared to [ 18 F]-fluorodeoxyglucose (FDG) PET in a clinical setting., Methods: All subjects were recruited with clinical suspicion of dementia due to neurodegenerative disease. FDG PET was undertaken by conventional methods, and amyloid PET was performed with FBB, with early recordings for the initial 10 min (early-phase FBB), and late recordings at 90-110 min p.i. (late-phase FBB). Regional SUVR with cerebellar and global mean normalization were calculated for early-phase FBB and FDG PET. Pearson correlation coefficients between FDG and early-phase FBB were calculated for predefined cortical brain regions. Furthermore, a visual interpretation of disease pattern using 3-dimensional stereotactic surface projections (3D-SSP) was performed, with assessment of intra-reader agreement., Results: Among a total of 33 patients (mean age 67.5 ± 11.0 years) included in the study, 18 were visually rated amyloid-positive, and 15 amyloid-negative based on late-phase FBB scans. Correlation coefficients for early-phase FBB vs. FDG scans displayed excellent agreement in all target brain regions for global mean normalization. Cerebellar normalization gave strong, but significantly lower correlations. 3D representations of early-phase FBB visually resembled the corresponding FDG PET images, irrespective of the amyloid-status of the late FBB scans., Conclusions: Early-phase FBB acquisitions correlate on a relative quantitative and visual level with FDG PET scans, irrespective of the amyloid plaque density assessed in late FBB imaging. Thus, early-phase FBB uptake depicts a metabolism-like image, suggesting it as a valid surrogate marker for synaptic dysfunction, which could ultimately circumvent the need for additional FDG PET investigation in diagnosis of dementia.

Purpose: Current guidelines for glioma imaging by positron emission tomography (PET) using the amino acid analogue O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) recommend image acquisition from 20-40 min post injection (p.i.). The maximal tumour-to-background evaluation (TBRmax) obtained in these summation images does not enable reliable differentiation between low and high grade glioma (LGG and HGG), which, however, can be achieved by dynamic (18)F-FET-PET. We investigated the accuracy of tumour grading using TBRmax values at different earlier time points after tracer injection., Methods: Three hundred and fourteen patients with histologically proven primary diagnosis of glioma (131 LGG, 183 HGG) who had undergone 40-min dynamic (18)F-FET-PET scans were retrospectively evaluated. TBRmax was assessed in the standard 20-40 min summation images, as well as in summation images from 0-10 min, 5-15 min, 5-20 min, and 15-30 min p.i., and kinetic analysis was performed. TBRmax values and kinetic analysis were correlated with histological classification. ROC analyses were performed for each time frame and sensitivity, specificity, and accuracy were assessed., Results: TBRmax values in the earlier summation images were significantly better for tumour grading (P < 0.001) when compared to standard 20-40 min scans, with best results for the early 5-15 min scan. This was due to higher TBRmax in the HGG (3.9 vs. 3.3; p < 0.001), while TBRmax remained nearly stable in the LGG (2.2 vs. 2.1). Overall, accuracy increased from 70 % in the 20-40 min analysis to 77 % in the 5-15 min images, but did not reach the accuracy of dynamic analysis (80 %)., Conclusions: Early TBRmax assessment (5-15 min p.i.) is more accurate for the differentiation between LGG and HGG than the standard static scan (20-40 min p.i.) mainly caused by the characteristic high (18)F-FET uptake of HGG in the initial phase. Therefore, when dynamic (18)F-FET-PET cannot be performed, early TBRmax assessment can be considered as an alternative for tumour grading.

Background: Raw PET list-mode data contains motion artifacts causing image blurring and decreased spatial resolution. Unless corrected, this leads to underestimation of the tracer uptake and overestimation of the lesion size, as well as inaccuracies with regard to left ventricular volume and ejection fraction (LVEF), especially in small animal imaging., Methods and Results: A respiratory trigger signal from respiration-induced variations in the electro-cardiogram (ECG) was detected. Original and revised list-mode PET data were used for calculation of left ventricular function parameters using both respiratory gating techniques. For adequately triggered datasets we saw no difference in mean respiratory cycle period between the reference standard (RRS) and the ECG-based (ERS) methods (1120 ± 159 ms vs 1120 ± 159 ms; P = n.s.). While the ECG-based method showed somewhat higher signal noise (66 ± 22 ms vs 51 ± 29 ms; P < .001), both respiratory triggering techniques yielded similar estimates for EDV, ESV, LVEF (RRS: 387 ± 56 µL, 162 ± 34 µL, 59 ± 5%; ERS: 389 ± 59 µL, 163 ± 35 µL, 59 ± 4%; P = n.s.)., Conclusions: This study showed that respiratory gating signals can be accurately derived from cardiac trigger information alone, without the additional requirement for dedicated measurement of the respiratory motion in rats.

Unlabelled: Human mesenchymal stem cells (hMSCs) represent a promising treatment approach for tissue repair and regeneration. However, little is known about the underlying mechanisms and the fate of the transplanted cells. The objective of the presented work was to determine the feasibility of PET imaging and in vivo monitoring after transplantation of dopamine type 2 receptor-expressing cells., Methods: An hMSC line constitutively expressing a mutant of the dopamine type 2 receptor (D2R80A) was generated by lentiviral gene transfer. D2R80A messenger RNA expression was confirmed by reverse transcriptase-polymerase chain reaction. Localization of the transmembrane protein was analyzed by confocal fluorescence microscopy. The stem cell character of transduced hMSCs was investigated by adipogenic and osteogenic differentiation. Migration capacity was assessed by scratch assays in time-lapse imaging. In vitro specific binding of ligands was tested by fluorescence-activated cell sorting analysis and by radioligand assay using (18)F-fallypride. Imaging of D2R80A overexpressing hMSC transplanted into athymic rats was performed by PET using (18)F-fallypride., Results: hMSCs showed long-term overexpression of D2R80A. As expected, the fluorescence signal suggested the primary localization of the protein in the membrane of the transduced cells. hMSC and D2R80A retained their stem cell character demonstrated by their osteogenic and adipogenic differentiation capacity and their proliferation and migration behavior. For in vitro hMSCs, at least 90% expressed the D2R80A transgene and hMSC-D2R80A showed specific binding of (18)F-fallypride. In vivo, a specific signal was detected at the transplantation site up to 7 d by PET., Conclusion: The mutant of the dopamine type 2 receptor (D2R80A) is a potent reporter to detect hMSCs by PET in vivo., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

The assessment of left ventricular function, wall motion and myocardial viability using electrocardiogram (ECG)-gated [(18)F]-FDG positron emission tomography (PET) is widely accepted in human and in preclinical small animal studies. The nonterminal and noninvasive approach permits repeated in vivo evaluations of the same animal, facilitating the assessment of temporal changes in disease or therapy response. Although well established, gated small animal PET studies can contain erroneous gating information, which may yield to blurred images and false estimation of functional parameters. In this work, we present quantitative and visual quality control (QC) methods to evaluate the accuracy of trigger events in PET list-mode and physiological data. Left ventricular functional analysis is performed to quantify the effect of gating errors on the end-systolic and end-diastolic volumes, and on the ejection fraction (EF). We aim to recover the cardiac functional parameters by the application of the commonly established heart rate filter approach using fixed ranges based on a standardized population. In addition, we propose a fully reprocessing approach which retrospectively replaces the gating information of the PET list-mode file with appropriate list-mode decoding and encoding software. The signal of a simultaneously acquired ECG is processed using standard MATLAB vector functions, which can be individually adapted to reliably detect the R-peaks. Finally, the new trigger events are inserted into the PET list-mode file. A population of 30 mice with various health statuses was analyzed and standard cardiac parameters such as mean heart rate (119 ms ± 11.8 ms) and mean heart rate variability (1.7 ms ± 3.4 ms) derived. These standard parameter ranges were taken into account in the QC methods to select a group of nine optimal gated and a group of eight sub-optimal gated [(18)F]-FDG PET scans of mice from our archive. From the list-mode files of the optimal gated group, we randomly deleted various fractions (5% to 60%) of contained trigger events to generate a corrupted group. The filter approach was capable to correct the corrupted group and yield functional parameters with no significant difference to the optimal gated group. We successfully demonstrated the potential of the fully reprocessing approach by applying it to the sub-optimal group, where the functional parameters were significantly improved after reprocessing (mean EF from 41% ± 16% to 60% ± 13%). When applied to the optimal gated group the fully reprocessing approach did not alter the functional parameters significantly (mean EF from 64% ± 8% to 64 ± 7%). This work presents methods to determine and quantify erroneous gating in small animal gated [(18)F]-FDG PET scans. We demonstrate the importance of a quality check for cardiac triggering contained in PET list-mode data and the benefit of optionally reprocessing the fully recorded physiological information to retrospectively modify or fully replace the cardiac triggering in PET list-mode data. We aim to provide a preliminary guideline of how to proceed in the presence of errors and demonstrate that offline reprocessing by filtering erroneous trigger events and retrospective gating by ECG processing is feasible. Future work will focus on the extension by additional QC methods, which may exploit the amplitude of trigger events and ECG signal by means of pattern recognition. Furthermore, we aim to transfer the proposed QC methods and the fully reprocessing approach to human myocardial PET/CT.

Unlabelled: The progression of β-amyloid deposition in the brains of mice overexpressing Swedish mutant β-amyloid precursor protein (APP-Swe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel β-amyloid tracer (18)F-florbetaben., Methods: Groups of APP-Swe and age-matched wild-type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of (18)F-florbetaben (9 MBq, intravenously). After spatial normalization of individual PET recordings to common coordinates for mouse brain, binding potentials (BPND) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of β-amyloid plaque load., Results: SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BPND based on the entire dynamic emission recordings. (18)F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P < 0.01) in cortical (18)F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P < 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P < 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R = 0.95, P < 0.001)., Conclusion: In the first longitudinal PET study in an AD mouse model using the novel β-amyloid tracer (18)F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD.

Unlabelled: Data collection in preclinical small-animal PET studies has been hindered by the small number of recordings typically obtained for a single radiosynthesis. Therefore, we tested procedures for obtaining 8 simultaneous small-animal PET recordings from the brains of 8 mice using an acrylic anesthesia distributor (the Octamouse), with the dopamine D(2/3) ligand (18)F-fallypride serving as a test substance for brain receptor imaging., Methods: The effect of scatter correction on the small-animal PET recordings was first evaluated in phantom studies in which sources of different radioactivity concentration were placed within the chambers of the Octamouse. Next, potential effects of mass on the (18)F-fallypride binding potential (BP(ND)) in the striatum were tested in groups of mice receiving (18)F-fallypride at 2 different specific activities (140 and 50 GBq/μmol), with and without scatter correction. Finally, the relationship between BP(ND) and injected dose of (18)F-fallypride (3.5-17 MBq/mouse) was tested., Results: Scatter correction improved the contrast between sources and air space within the Octamouse phantom. The magnitude of (18)F-fallypride BP(ND) in mouse striatum was invariant across the tested range of specific activities, and scatter correction increased BP(ND) by a mean of 6%; covariances of the inter- and intraoperator variability of BP(ND) were 10%. There was a positive correlation between radiochemical dose and BP(ND) with (R(2) = 0.53) and without (R(2) = 0.63) scatter correction, which was driven by increasing area under the percentage injected dose curve in the striatum., Conclusion: The quantitation of emission sources placed within the Octamouse is linear over a wide range of source activities. In the striatum of living mice, the magnitude of (18)F-fallypride BP(ND) was highly reproducible between operators and was constant over a 3-fold range of specific activities, indicating a lack of significant occupancy. Scatter correction improved quantitation but did not entirely correct for the dependence of BP(ND) on injected dose, which was deemed to arise because of effects propagating from detector dead time when the total radiochemical dose in the field of view exceeded 50 MBq. Given this consideration, we were still able to quantify (18)F-fallypride BP(ND) in 16 mice from a single radiosynthesis, an economy that should be generalizable to brain studies of diverse radioligands.