Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive. METHODS: Combining magnetic resonance (MR) spectroscopy and [11C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (VT) of [11C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia. RESULTS: We measured globally elevated VT of [11C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of [11C]ABP688. VT of [11C]ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023) and with dopaminergic treatment response in patients with PD (F(1,30) = 5.823, p = 0.022). DISCUSSION: Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher VT of [11C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.

Impact of framing scheme optimization and smoking status on binding potential analysis in dynamic PET with [11C]ABP688.

BACKGROUND: For positron emission tomography (PET) ligands, such as [11C]ABP688, to be able to provide more evidence about the glutamatergic hypothesis in schizophrenia (SZ), quantification bias during dynamic PET studies and its propagation into the estimated values of non-displaceable binding potential (BPND) must be addressed. This would enable more accurate quantification during bolus + infusion (BI) neuroreceptor studies and further our understanding of neurological diseases. Previous studies have shown BPND-related biases can often occur due to overestimated cerebellum activity (reference region). This work investigates whether an alternative framing scheme can minimize quantification biases propagated into BPND, whether confounders, such as smoking status, need to be controlled for during the study, and what the consequences for the data interpretation following analysis are. A group of healthy controls (HC) and a group of SZ patients (balanced and unbalanced number of smokers) were investigated with [11C]ABP688 and a BI protocol. Possible differences in BPND quantification as a function of smoking status were tested with constant 5 min ('Const 5 min') and constant true counts ('Const Trues') framing schemes. In order to find biomarkers for SZ, the differences in smoking effects were compared between groups. The normalized BPND and the balanced number of smokers and non-smokers for both framing schemes were evaluated. RESULTS: When applying F-tests to the 'Const 5 min' framing scheme, effect sizes (η2p) and brain regions which showed significant effects fluctuated considerably with F = 50.106 ± 54.948 (9.389 to 112.607), P-values 0.005 to < 0.001 and η2p = 0.514 ± 0.282 (0.238 to 0.801). Conversely, when the 'Const Trues' framing scheme was applied, the results showed much smaller fluctuations with F = 78.038 ± 8.975 (86.450 to 68.590), P < 0.001 for all conditions and η2p = 0.730 ± 0.017 (0.742 to 0.710), and regions with significant effects were more robustly reproduced. Further, differences, which would indicate false positive identifications between HC and SZ groups in five brain regions when using the 'Const 5 min' framing scheme, were not observed with the 'Const Trues' framing. CONCLUSIONS: Based on an [11C]ABP688 PET study in SZ patients, the results show that non-consistent BPND outcomes can be propagated by the framing scheme and that potential bias can be minimized using 'Const Trues' framing.

mGluR5 binding changes during a mismatch negativity task in a multimodal protocol with [11C]ABP688 PET/MR-EEG.

Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [11C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BPND) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BPND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall's W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BPND changes. There was a significant ΔBPND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBPND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes.

A Linearized Fit Model for Robust Shape Parameterization of FET-PET TACs.

The kinetic analysis of [Formula: see text]-FET time-activity curves (TAC) can provide valuable diagnostic information in glioma patients. The analysis is most often limited to the average TAC over a large tissue volume and is normally assessed by visual inspection or by evaluating the time-to-peak and linear slope during the late uptake phase. Here, we derived and validated a linearized model for TACs of [Formula: see text]-FET in dynamic PET scans. Emphasis was put on the robustness of the numerical parameters and how reliably automatic voxel-wise analysis of TAC kinetics was possible. The diagnostic performance of the extracted shape parameters for the discrimination between isocitrate dehydrogenase (IDH) wildtype (wt) and IDH-mutant (mut) glioma was assessed by receiver-operating characteristic in a group of 33 adult glioma patients. A high agreement between the adjusted model and measured TACs could be obtained and relative, estimated parameter uncertainties were small. The best differentiation between IDH-wt and IDH-mut gliomas was achieved with the linearized model fitted to the averaged TAC values from dynamic FET PET data in the time interval 4-50 min p.i.. When limiting the acquisition time to 20-40 min p.i., classification accuracy was only slightly lower (-3%) and was comparable to classification based on linear fits in this time interval. Voxel-wise fitting was possible within a computation time ≈ 1 min per image slice. Parameter uncertainties smaller than 80% for all fits with the linearized model were achieved. The agreement of best-fit parameters when comparing voxel-wise fits and fits of averaged TACs was very high (p < 0.001).

Bias evaluation and reduction in 3D OP-OSEM reconstruction in dynamic equilibrium PET studies with 11C-labeled for binding potential analysis.

Iterative image reconstruction is widely used in positron emission tomography. However, it is known to contribute to quantitation bias and is particularly pronounced during dynamic studies with 11C-labeled radiotracers where count rates become low towards the end of the acquisition. As the strength of the quantitation bias depends on the counts in the reconstructed frame, it can differ from frame to frame of the acquisition. This is especially relevant in the case of neuro-receptor studies with simultaneous PET/MR when a bolus-infusion protocol is applied to allow the comparison of pre- and post-task effects. Here, count dependent changes in quantitation bias may interfere with task changes. We evaluated the impact of different framing schemes on quantitation bias and its propagation into binding potential (BP) using a phantom decay study with 11C and 3D OP-OSEM. Further, we propose a framing scheme that keeps the true counts per frame constant over the acquisition time as constant framing schemes and conventional increasing framing schemes are unlikely to achieve stable bias values during the acquisition time range. For a constant framing scheme with 5 minutes frames, the BP bias was 7.13±2.01% (10.8% to 3.8%) compared to 5.63±2.85% (7.8% to 4.0%) for conventional increasing framing schemes. Using the proposed constant true counts framing scheme, a stabilization of the BP bias was achieved at 2.56±3.92% (3.5% to 1.7%). The change in BP bias was further studied by evaluating the linear slope during the acquisition time interval. The lowest slope values were observed in the constant true counts framing scheme. The constant true counts framing scheme was effective for BP bias stabilization at relevant activity and time ranges. The mean BP bias under these conditions was 2.56±3.92%, which represents the lower limit for the detection of changes in BP during equilibrium and is especially important in the case of cognitive tasks where the expected changes are low.

FET PET Radiomics for Differentiating Pseudoprogression from Early Tumor Progression in Glioma Patients Post-Chemoradiation.

Currently, a reliable diagnostic test for differentiating pseudoprogression from early tumor progression is lacking. We explored the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) radiomics for this clinically important task. Thirty-four patients (isocitrate dehydrogenase (IDH)-wildtype glioblastoma, 94%) with progressive magnetic resonance imaging (MRI) changes according to the Response Assessment in Neuro-Oncology (RANO) criteria within the first 12 weeks after completing temozolomide chemoradiation underwent a dynamic FET PET scan. Static and dynamic FET PET parameters were calculated. For radiomics analysis, the number of datasets was increased to 102 using data augmentation. After randomly assigning patients to a training and test dataset, 944 features were calculated on unfiltered and filtered images. The number of features for model generation was limited to four to avoid data overfitting. Eighteen patients were diagnosed with early tumor progression, and 16 patients had pseudoprogression. The FET PET radiomics model correctly diagnosed pseudoprogression in all test cohort patients (sensitivity, 100%; negative predictive value, 100%). In contrast, the diagnostic performance of the best FET PET parameter (TBRmax) was lower (sensitivity, 81%; negative predictive value, 80%). The results suggest that FET PET radiomics helps diagnose patients with pseudoprogression with a high diagnostic performance. Given the clinical significance, further studies are warranted.

PET attenuation correction for rigid MR Tx/Rx coils from 176Lu background activity.

One challenge for PET-MR hybrid imaging is the correction for attenuation of the 511 keV annihilation radiation by the required RF transmit and/or RF receive coils. Although there are strategies for building PET transparent Tx/Rx coils, such optimised coils still cause significant attenuation of the annihilation radiation leading to artefacts and biases in the reconstructed activity concentrations. We present a straightforward method to measure the attenuation of Tx/Rx coils in simultaneous MR-PET imaging based on the natural 176Lu background contained in the scintillator of the PET detector without the requirement of an external CT scanner or PET scanner with transmission source. The method was evaluated on a prototype 3T MR-BrainPET produced by Siemens Healthcare GmbH, both with phantom studies and with true emission images from patient/volunteer examinations. Furthermore, the count rate stability of the PET scanner and the x-ray properties of the Tx/Rx head coil were investigated. Even without energy extrapolation from the two dominant γ energies of 176Lu to 511 keV, the presented method for attenuation correction, based on the measurement of 176Lu background attenuation, shows slightly better performance than the coil attenuation correction currently used. The coil attenuation correction currently used is based on an external transmission scan with rotating 68Ge sources acquired on a Siemens ECAT HR + PET scanner. However, the main advantage of the presented approach is its straightforwardness and ready availability without the need for additional accessories.

Maximum likelihood positioning and energy correction for scintillation detectors.

An algorithm for determining the crystal pixel and the gamma ray energy with scintillation detectors for PET is presented. The algorithm uses Likelihood Maximisation (ML) and therefore is inherently robust to missing data caused by defect or paralysed photo detector pixels. We tested the algorithm on a highly integrated MRI compatible small animal PET insert. The scintillation detector blocks of the PET gantry were built with the newly developed digital Silicon Photomultiplier (SiPM) technology from Philips Digital Photon Counting and LYSO pixel arrays with a pitch of 1 mm and length of 12 mm. Light sharing was used to readout the scintillation light from the 30 × 30 scintillator pixel array with an 8 × 8 SiPM array. For the performance evaluation of the proposed algorithm, we measured the scanner's spatial resolution, energy resolution, singles and prompt count rate performance, and image noise. These values were compared to corresponding values obtained with Center of Gravity (CoG) based positioning methods for different scintillation light trigger thresholds and also for different energy windows. While all positioning algorithms showed similar spatial resolution, a clear advantage for the ML method was observed when comparing the PET scanner's overall single and prompt detection efficiency, image noise, and energy resolution to the CoG based methods. Further, ML positioning reduces the dependence of image quality on scanner configuration parameters and was the only method that allowed achieving highest energy resolution, count rate performance and spatial resolution at the same time.

Software-Based Real-Time Acquisition and Processing of PET Detector Raw Data.

In modern positron emission tomography (PET) readout architectures, the position and energy estimation of scintillation events (singles) and the detection of coincident events (coincidences) are typically carried out on highly integrated, programmable printed circuit boards. The implementation of advanced singles and coincidence processing (SCP) algorithms for these architectures is often limited by the strict constraints of hardware-based data processing. In this paper, we present a software-based data acquisition and processing architecture (DAPA) that offers a high degree of flexibility for advanced SCP algorithms through relaxed real-time constraints and an easily extendible data processing framework. The DAPA is designed to acquire detector raw data from independent (but synchronized) detector modules and process the data for singles and coincidences in real-time using a center-of-gravity (COG)-based, a least-squares (LS)-based, or a maximum-likelihood (ML)-based crystal position and energy estimation approach (CPEEA). To test the DAPA, we adapted it to a preclinical PET detector that outputs detector raw data from 60 independent digital silicon photomultiplier (dSiPM)-based detector stacks and evaluated it with a [(18)F]-fluorodeoxyglucose-filled hot-rod phantom. The DAPA is highly reliable with less than 0.1% of all detector raw data lost or corrupted. For high validation thresholds (37.1 ± 12.8 photons per pixel) of the dSiPM detector tiles, the DAPA is real time capable up to 55 MBq for the COG-based CPEEA, up to 31 MBq for the LS-based CPEEA, and up to 28 MBq for the ML-based CPEEA. Compared to the COG-based CPEEA, the rods in the image reconstruction of the hot-rod phantom are only slightly better separable and less blurred for the LS- and ML-based CPEEA. While the coincidence time resolution (∼ 500 ps) and energy resolution (∼12.3%) are comparable for all three CPEEA, the system sensitivity is up to 2.5 × higher for the LS- and ML-based CPEEA.

A Digital Preclinical PET/MRI Insert and Initial Results.

Combining Positron Emission Tomography (PET) with Magnetic Resonance Imaging (MRI) results in a promising hybrid molecular imaging modality as it unifies the high sensitivity of PET for molecular and cellular processes with the functional and anatomical information from MRI. Digital Silicon Photomultipliers (dSiPMs) are the digital evolution in scintillation light detector technology and promise high PET SNR. DSiPMs from Philips Digital Photon Counting (PDPC) were used to develop a preclinical PET/RF gantry with 1-mm scintillation crystal pitch as an insert for clinical MRI scanners. With three exchangeable RF coils, the hybrid field of view has a maximum size of 160 mm × 96.6 mm (transaxial × axial). 0.1 ppm volume-root-mean-square B 0-homogeneity is kept within a spherical diameter of 96 mm (automatic volume shimming). Depending on the coil, MRI SNR is decreased by 13% or 5% by the PET system. PET count rates, energy resolution of 12.6% FWHM, and spatial resolution of 0.73 mm (3) (isometric volume resolution at isocenter) are not affected by applied MRI sequences. PET time resolution of 565 ps (FWHM) degraded by 6 ps during an EPI sequence. Timing-optimized settings yielded 260 ps time resolution. PET and MR images of a hot-rod phantom show no visible differences when the other modality was in operation and both resolve 0.8-mm rods. Versatility of the insert is shown by successfully combining multi-nuclei MRI ((1)H/(19)F) with simultaneously measured PET ((18)F-FDG). A longitudinal study of a tumor-bearing mouse verifies the operability, stability, and in vivo capabilities of the system. Cardiac- and respiratory-gated PET/MRI motion-capturing (CINE) images of the mouse heart demonstrate the advantage of simultaneous acquisition for temporal and spatial image registration.

MR compatibility aspects of a silicon photomultiplier-based PET/RF insert with integrated digitisation.

The combination of Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) into a single device is being considered a promising tool for molecular imaging as it combines the high sensitivity of PET with the functional and anatomical images of MRI. For highest performance, a scalable, MR compatible detector architecture with a small form factor is needed, targeting at excellent PET signal-to-noise ratios and time-of-flight information. Therefore it is desirable to use silicon photo multipliers and to digitize their signals directly in the detector modules inside the MRI bore. A preclinical PET/RF insert for clinical MRI scanner was built to demonstrate a new architecture and to study the interactions between the two modalities.The disturbance of the MRI's static magnetic field stays below 2 ppm peak-to-peak within a diameter of 56 mm (90 mm using standard automatic volume shimming). MRI SNR is decreased by 14%, RF artefacts (dotted lines) are only visible in sequences with very low SNR. Ghosting artefacts are visible to the eye in about 26% of the EPI images, severe ghosting only in 7.6%. Eddy-current related heating effects during long EPI sequences are noticeable but with low influence of 2% on the coincidences count rate. The time resolution of 2.5 ns, the energy resolution of 29.7% and the volumetric spatial resolution of 1.8 mm(3) in the PET isocentre stay unaffected during MRI operation. Phantom studies show no signs of other artefacts or distortion in both modalities. A living rat was simultaneously imaged after the injection with (18)F-Fluorodeoxyglucose (FDG) proving the in vivo capabilities of the system.