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

Brambilla, Cláudia Régio; Veselinović, Tanja; Rajkumar, Ravichandran; Mauler, Jörg; Matusch, Andreas; Ruch, Andrej; Orth, Linda; Ramkiran, Shukti; Sbaihat, Hasan; Kaulen, Nicolas; Khudeish, Nibal Yahya; Wyss, Christine; Kawohl, Wolfram; Kops, Elena Rota; Tellmann, Lutz; Scheins, J.; Boers, Frank; Neumaier, Bernd; Lang, Markus; Stüsgen, Stefan; Herzog, Hans; Langen, Karl‐Josef; Shah, N. Jon; Lerche, Christoph; Neuner, Irene

doi:10.1038/s41398-021-01763-3

Cited by 12 publications

(11 citation statements)

References 72 publications

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“…Although, in this case, the effect of the global DTC compared to the block-pairwise DTC was rather small, there was a 2% difference in the BP ND . This difference can potentially mask the effects of cognitive challenges as described in (Régio Brambilla et al 2022), as it decreases over time and alters for different brain regions. Despite not being relevant for the present bolus-infusion protocol investigation, the early part of the TACs allow an important conclusion for dynamic studies using a bolus injection protocol and kinetic modeling to be drawn, which requires evaluation of the entire TAC to derive the BP ND outcome.…”

Section: Discussionmentioning

confidence: 99%

“…No further data processing was conducted for the phantom measurements. Constant true coincidence count rate framing schemes were used in all reconstructions to minimize reconstruction bias at low counts (Brambilla et al 2021, Régio Brambilla et al 2022). In the third measurement (III), five circular ROIs were specified in each compartment to enable the evaluation of accuracy and noise level.…”

Section: Methodsmentioning

confidence: 99%

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A Detector Block-Pairwise Dead Time Correction Method for Improved Quantitation with a Dedicated BrainPET Scanner

Issa

Scheins

Tellmann

et al. 2022

Preprint

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Dead time correction (DTC) is an important factor in ensuring accurate quantification in PET measurements. This is currently often achieved using a global DTC method, i.e., an average DTC factor is computed. For PET scanners designed to image dedicated organs, e.g., those used in brain imaging or positron emission mammography (PEM), a substantial amount of the administered radioactivity is located outside of the PET field-of-view (FOV). This activity contributes to the dead time (DT) of the scintillation detectors. Moreover, the count rates of the individual scintillation detectors are potentially very inhomogeneous due to the specific irradiation of each detector, especially for combined MR/PET systems, where radiation shields cannot be applied. We have developed a block-pairwise DTC method for our Siemens 3T MR BrainPET insert by extending a previously published method that uses the delayed random coincidence count rate to estimate the DT in the individual scans and planes (i.e., scintillation pixel rings). The method was validated in decay experiments using phantoms with a homogenous activity concentration and with and without out-of-FOV activity. Based on a three-compartment phantom, we compared the accuracy and noise properties of the block-pairwise DTC and the global DTC method. While the currently used global DTC led to a substantial positive bias in regions with high activity, the block-pairwise DTC resulted in substantially less bias. The noise level for the block-pairwise DTC was comparable to the global DTC and image reconstructions without any DTC. Finally, we tested the block-pairwise DTC with a data set obtained from volunteer measurements using the mGlu5R (metabotropic glutamate receptor subtype 5) antagonist [ 11 C]-ABP688, when comparing the time-activity curves (TACs) obtained with the global DTC with the block-pairwise DTC, relative differences in the anterior cingulate cortex (ACC) and the cerebellum of up to 25% were observed during the first 30 minutes of these measurements.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A Detector Block-Pairwise Dead Time Correction Method for Improved Quantitation with a Dedicated BrainPET Scanner

Issa

Scheins

Tellmann

et al. 2022

Preprint

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“…In order to obtain metabolite-corrected plasma concentrations, the parent compound was separated from the metabolites in each sample by solid-phase extraction using appropriate cartridges (Waters Sep-Pak® tC18) as previously described. 29 Again, steady-state conditions of plasma activities during 45 - 60 min post bolus injection were ascertained visually and by a low coefficient of variance (mean, 4.8 ± 2.5%), and we averaged all four metabolite-corrected plasma concentrations. We calculated regional brain V T as follows: The radioligand concentration in the VOI (mean of 45 - 60 min) divided by metabolite-corrected plasma concentration (mean of 45 - 60 min).…”

Section: Methodsmentioning

confidence: 99%

Altered glutamate signaling in Parkinson’s disease patients with REM sleep behavior disorder

Doppler

Seger

Farrher

et al. 2023

Preprint

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Background and Objectives: Clinical heterogeneity of patients with Parkinson′s disease is well recognized. Parkinson′s disease with rapid eye movement (REM) sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher non-motor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning disbalances in neurotransmitter systems remain elusive. Methods: Combining magnetic resonance (MR) spectroscopy and 11C-ABP688 positron emission tomography (PET) on PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with Parkinson′s disease. Thirty-three patients were grouped according to their RBD status in overnight video-polysomnography and compared to 15 age- and sex-matched healthy control (HC) subjects. Total volumes of distribution (VT) of 11C-ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between minutes 45 to 60 of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single voxel STEAM MR spectroscopy of the left putamen. Results: We measured globally elevated VT of 11C-ABP688 in patients with Parkinson′s disease and RBD compared to patients without RBD and HC subjects (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 Parkinson′s disease patients (F(1,30) = 5.823, p = 0.022). Conclusion: Our results suggest that patients with Parkinson′s disease and RBD exhibit altered glutamatergic signaling indicated by higher VT of 11C-ABP688 despite unaffected glutamate metabolism. The disbalance of glutamate receptors and neurotransmitter might indicate a novel mechanism contributing to the heterogeneity of Parkinson′s disease and warrants further investigation of drugs targeting mGluR5.

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“…In the first reconstruction, the listmode data were sorted into 5 min frames ('Const 5 min'). In the second reconstruction, the frames were reconstructed according to a method already presented [11,21] with a constant number of true coincidences in each frame ('Const Trues'), which minimizes and keeps the bias constant. For the 'Const Trues' scheme, PET true counts per frame based on this scheme were equivalent between subjects and also synchronized according to the fMRI RS acquisition moment.…”

Section: Pet Image Reconstruction and Bp Nd Estimationmentioning

confidence: 99%

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

et al. 2023

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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.

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

Cited by 12 publications

References 72 publications

A Detector Block-Pairwise Dead Time Correction Method for Improved Quantitation with a Dedicated BrainPET Scanner

A Detector Block-Pairwise Dead Time Correction Method for Improved Quantitation with a Dedicated BrainPET Scanner

Altered glutamate signaling in Parkinson’s disease patients with REM sleep behavior disorder

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

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