Exploring Vessel Wall Biology In Vivo by Ultrasensitive Total-Body PET.

Ultrasensitive, high-resolution, extended-field-of-view total-body (TB) PET using the first-of-its-kind 194-cm axial-field-of-view uEXPLORER may facilitate the interrogation of biologic hallmarks of hitherto difficult-to-evaluate low-signal vessel wall pathology in cardiovascular disease. Methods: Healthy volunteers were imaged serially for up to 12 h after a standard dose of 18F-FDG (n = 15) or for up to 3 h after injection of a very low dose (about 5% of a standard dose; n = 15). A cohort undergoing standard 18F-FDG PET (n = 15) on a conventional scanner with a 22-cm axial field of view served as a comparison group. Arterial wall signal, crosstalk with hematopoietic and lymphoid organs, and image quality were analyzed using standardized techniques. Results: TB PET depicted the large vessel walls with excellent quality. The arterial wall could be imaged with high contrast up to 12 h after tracer injection. Ultralow-dose TB 18F-FDG images yielded a vessel wall signal and target-to-background ratio comparable to those of conventional-dose, short-axial-field-of-view PET. Crosstalk between vessel wall and lymphoid organs was identified with better accuracy in both TB PET cohorts than in conventional PET. Conclusion: TB PET enables detailed assessment of in vivo vessel wall biology and its crosstalk with other organs over an extended time window after tracer injection or at an ultralow tracer dose. These initial observations support the feasibility of serial imaging in low-risk populations and will stimulate future mechanistic studies or therapy monitoring in atherosclerosis and other vessel wall pathologies.

Reduced microglia activity in patients with long-term immunosuppressive therapy after liver transplantation.

PURPOSE: Calcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand 18F-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression. METHODS: PET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (VT) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance. RESULTS: In controls, VT was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean VT corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect. CONCLUSION: Our results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity.

Combined Brain-Perfusion SPECT and EEG Measurements Suggest Distinct Strategies for Speech Comprehension in CI Users With Higher and Lower Performance.

Cochlear implantation constitutes a successful therapy of inner ear deafness, with the majority of patients showing good outcomes. There is, however, still some unexplained variability in outcomes with a number of cochlear-implant (CI) users, showing major limitations in speech comprehension. The current study used a multimodal diagnostic approach combining single-photon emission computed tomography (SPECT) and electroencephalography (EEG) to examine the mechanisms underlying speech processing in postlingually deafened CI users (N = 21). In one session, the participants performed a speech discrimination task, during which a 96-channel EEG was recorded and the perfusions marker 99mTc-HMPAO was injected intravenously. The SPECT scan was acquired 1.5 h after injection to measure the cortical activity during the speech task. The second session included a SPECT scan after injection without stimulation at rest. Analysis of EEG and SPECT data showed N400 and P600 event-related potentials (ERPs) particularly evoked by semantic violations in the sentences, and enhanced perfusion in a temporo-frontal network during task compared to rest, involving the auditory cortex bilaterally and Broca's area. Moreover, higher performance in testing for word recognition and verbal intelligence strongly correlated to the activation in this network during the speech task. However, comparing CI users with lower and higher speech intelligibility [median split with cutoff + 7.6 dB signal-to-noise ratio (SNR) in the Göttinger sentence test] revealed for CI users with higher performance additional activations of parietal and occipital regions and for those with lower performance stronger activation of superior frontal areas. Furthermore, SPECT activity was tightly coupled with EEG and cognitive abilities, as indicated by correlations between (1) cortical activation and the amplitudes in EEG, N400 (temporal and occipital areas)/P600 (parietal and occipital areas) and (2) between cortical activation in left-sided temporal and bilateral occipital/parietal areas and working memory capacity. These results suggest the recruitment of a temporo-frontal network in CI users during speech processing and a close connection between ERP effects and cortical activation in CI users. The observed differences in speech-evoked cortical activation patterns for CI users with higher and lower speech intelligibility suggest distinct processing strategies during speech rehabilitation with CI.

Reliable quantification of 18F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio.

PURPOSE: Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18F-GE-180. This study tested simplified methods for quantification of 18F-GE-180 PET. METHODS: Dynamic 18F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18F-GE-180 distribution volume (VT) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed. RESULTS: Correlation with the reference VT (with individually measured input function) was very high for VT with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for VT with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference VT, population-based VT with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based VT with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect. CONCLUSION: These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18F-GE-180 PET.

Reproducibility and Comparability of Preclinical PET Imaging Data: A Multicenter Small-Animal PET Study.

The standardization of preclinical imaging is a key factor to ensure the reliability, reproducibility, validity, and translatability of preclinical data. Preclinical standardization has been slowly progressing in recent years and has mainly been performed within a single institution, whereas little has been done in regards to multicenter standardization between facilities. This study aimed to investigate the comparability among preclinical imaging facilities in terms of PET data acquisition and analysis. In the first step, basic PET scans were obtained in 4 different preclinical imaging facilities to compare their standard imaging protocol for 18F-FDG. In the second step, the influence of the personnel performing the experiments and the experimental equipment used in the experiment were compared. In the third step, the influence of the image analysis on the reproducibility and comparability of the acquired data was determined. Distinct differences in the uptake behavior of the 4 standard imaging protocols were determined for the investigated organs (brain, left ventricle, liver, and muscle) due to different animal handling procedures before and during the scans (e.g., fasting vs. nonfasting, glucose levels, temperature regulation vs. constant temperature warming). Significant differences in the uptake behavior in the brain were detected when the same imaging protocol was used but executed by different personnel and using different experimental animal handling equipment. An influence of the person analyzing the data was detected for most of the organs, when the volumes of interest were manually drawn by the investigators. Coregistration of the PET to an MR image and drawing the volume of interest based on anatomic information yielded reproducible results among investigators. It has been demonstrated that there is a huge demand for standardization among multiple institutions.

Visualization of the auditory pathway in rats with 18F-FDG PET activation studies based on different auditory stimuli and reference conditions including cochlea ablation.

Activation studies with positron emission tomography (PET) in auditory implant users explained some of the mechanisms underlying the variability of achieved speech comprehension. Since future developments of auditory implants will include studies in rodents, we aimed to inversely translate functional PET imaging to rats. In normal hearing rats, activity in auditory and non-auditory regions was studied using 18F-fluorodeoxyglucose (18F-FDG) PET with 3 different acoustic conditions: sound attenuated laboratory background, continuous white noise and rippled noise. Additionally, bilateral cochlea ablated animals were scanned. 3D image data were transferred into a stereotaxic standard space and evaluated using volume of interest (VOI) analyses and statistical parametric mapping (SPM). In normal hearing rats alongside the auditory pathway consistent activations of the nucleus cochlearis (NC), olivary complex (OC) and inferior colliculus (IC) were seen comparing stimuli with background. In this respect, no increased activation could be detected in the auditory cortex (AC), which even showed deactivation with white noise stimulation. Nevertheless, higher activity in the AC in normal hearing rats was observed for all 3 auditory conditions against the cochlea ablated status. Vice versa, in ablated status activity in the olfactory nucleus (ON) was higher compared to all auditory conditions in normal hearing rats. Our results indicate that activations can be demonstrated in normal hearing animals based on 18F-FDG PET in nuclei along the central auditory pathway with different types of noise stimuli. However, in the AC missing activation with respect to the background advises the need for more rigorous background noise attenuation for non-invasive reference conditions. Finally, our data suggest cross-modal activation of the olfactory system following cochlea ablation-underlining, that 18F-FDG PET appears to be well suited to study plasticity in rat models for cochlear implantation.

Feasibility of 15O-water PET studies of auditory system activation during general anesthesia in children.

BACKGROUND: 15O-Water positron emission tomography (PET) enables functional imaging of the auditory system during stimulation via a promontory electrode or cochlear implant, which is not possible using functional magnetic resonance imaging (fMRI). Although PET has been introduced in this context decades ago, its feasibility when performed during general anesthesia has not yet been explored. However, due to a shift to earlier (and bilateral) auditory implantation, the need to study children during general anesthesia appeared, since they are not able to cooperate during scanning. Therefore, we evaluated retrospectively results of individual SPM (statistical parametric mapping) analysis of 15O-water PET in 17 children studied during general anesthesia and compared them to those in 9 adults studied while awake. Specifically, the influence of scan duration, smoothing filter kernel employed during preprocessing, and cut-off value used for statistical inferences were evaluated. Frequencies, peak heights, and extents of activations in auditory and extra-auditory brain regions (AR and eAR) were registered. RESULTS: It was possible to demonstrate activations in auditory brain regions during general anesthesia; however, the frequency and markedness of positive findings were dependent on some of the abovementioned influence factors. Scan duration (60 vs. 90 s) had no significant influence on peak height of auditory cortex activations. To achieve a similar frequency and extent of AR activations during general anesthesia compared to waking state, a lower cut-off for statistical inferences (p < 0.05 or p < 0.01 vs. p < 0.001) had to be applied. However, this lower cut-off was frequently associated with unexpected, "artificial" activations in eAR. These activations in eAR could be slightly reduced by the use of a stronger smoothing filter kernel during preprocessing of the data (e.g., [30 mm]3). CONCLUSIONS: Our data indicate that it is feasible to detect auditory cortex activations in 15O-water PET during general anesthesia. Combined with the improved signal to noise ratios of modern PET scanners, this suggests reasonable prospects for further evaluation of the method for clinical use in auditory implant users. Adapted parameters for data analysis seem to be helpful to improve the proportion of signals in AR versus eAR.

Multiple Time-Point 68Ga-PSMA I&T PET/CT for Characterization of Primary Prostate Cancer: Value of Early Dynamic and Delayed Imaging.

PURPOSE: The aims of this study were to gain mechanistic insights into prostate cancer biology using dynamic imaging and to evaluate the usefulness of multiple time-point Ga-prostate-specific membrane antigen (PSMA) I&T PET/CT for the assessment of primary prostate cancer before prostatectomy. METHODS: Twenty patients with prostate cancer underwent Ga-PSMA I&T PET/CT before prostatectomy. The PET protocol consisted of early dynamic pelvic imaging, followed by static scans at 60 and 180 minutes postinjection (p.i.). SUVs, time-activity curves, quantitative analysis based on a 2-tissue compartment model, Patlak analysis, histopathology, and Gleason grading were compared between prostate cancer and benign prostate gland. RESULTS: Primary tumors were identified on both early dynamic and delayed imaging in 95% of patients. Tracer uptake was significantly higher in prostate cancer compared with benign prostate tissue at any time point (P ≤ 0.0003) and increased over time. Consequently, the tumor-to-nontumor ratio within the prostate gland improved over time (2.8 at 10 minutes vs 17.1 at 180 minutes p.i.). Tracer uptake at both 60 and 180 minutes p.i. was significantly higher in patients with higher Gleason scores (P < 0.01). The influx rate (Ki) was higher in prostate cancer than in reference prostate gland (0.055 [r = 0.998] vs 0.017 [r = 0.996]). CONCLUSIONS: Primary prostate cancer is readily identified on early dynamic and static delayed Ga-PSMA ligand PET images. The tumor-to-nontumor ratio in the prostate gland improves over time, supporting a role of delayed imaging for optimal visualization of prostate cancer.

Positron Emission Tomography Imaging Reveals Auditory and Frontal Cortical Regions Involved with Speech Perception and Loudness Adaptation.

Considerable progress has been made in the treatment of hearing loss with auditory implants. However, there are still many implanted patients that experience hearing deficiencies, such as limited speech understanding or vanishing perception with continuous stimulation (i.e., abnormal loudness adaptation). The present study aims to identify specific patterns of cerebral cortex activity involved with such deficiencies. We performed O-15-water positron emission tomography (PET) in patients implanted with electrodes within the cochlea, brainstem, or midbrain to investigate the pattern of cortical activation in response to speech or continuous multi-tone stimuli directly inputted into the implant processor that then delivered electrical patterns through those electrodes. Statistical parametric mapping was performed on a single subject basis. Better speech understanding was correlated with a larger extent of bilateral auditory cortex activation. In contrast to speech, the continuous multi-tone stimulus elicited mainly unilateral auditory cortical activity in which greater loudness adaptation corresponded to weaker activation and even deactivation. Interestingly, greater loudness adaptation was correlated with stronger activity within the ventral prefrontal cortex, which could be up-regulated to suppress the irrelevant or aberrant signals into the auditory cortex. The ability to detect these specific cortical patterns and differences across patients and stimuli demonstrates the potential for using PET to diagnose auditory function or dysfunction in implant patients, which in turn could guide the development of appropriate stimulation strategies for improving hearing rehabilitation. Beyond hearing restoration, our study also reveals a potential role of the frontal cortex in suppressing irrelevant or aberrant activity within the auditory cortex, and thus may be relevant for understanding and treating tinnitus.