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- Laurell, Gjertrud L, et al.
(författare)
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Nondisplaceable Binding Is a Potential Confounding Factor in 11C-PBR28 Translocator Protein PET Studies.
- 2021
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 62:3, s. 412-417
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Tidskriftsartikel (refereegranskat)abstract
- The PET ligand 11C-PBR28 (N-((2-(methoxy-11C)-phenyl)methyl)-N-(6-phenoxy-3-pyridinyl)acetamide) binds to the 18-kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, VT, is frequently the reported outcome measure. Since VT is the sum of the ligand-specific distribution volume (VS) and the nondisplaceable-binding distribution volume (VND), differences in VND across subjects and groups will have an impact on VTMethods: Here, we used a recently developed method for simultaneous estimation of VND (SIME) to disentangle contributions from VND and VS Data from 4 previously published 11C-PBR28 PET studies were included: before and after a lipopolysaccharide challenge (8 subjects), in alcohol use disorder (14 patients, 15 controls), in first-episode psychosis (16 patients, 16 controls), and in Parkinson disease (16 patients, 16 controls). In each dataset, regional VT estimates were obtained with a standard 2-tissue-compartment model, and brain-wide VND was estimated with SIME. VS was then calculated as VT - VND VND and VS were then compared across groups, within each dataset. Results: A lower VND was found for individuals with alcohol-use disorder (34%, P = 0.00084) and Parkinson disease (34%, P = 0.0032) than in their corresponding controls. We found no difference in VND between first-episode psychosis patients and their controls, and the administration of lipopolysaccharide did not change VNDConclusion: Our findings suggest that in TSPO PET studies, nondisplaceable binding can differ between patient groups and conditions and should therefore be considered.
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| 2. |
- Matheson, Granville J., et al.
(författare)
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Assessment of simplified ratio-based approaches for quantification of PET [11C] PBR28 data
- 2017
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Ingår i: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Kinetic modelling with metabolite-corrected arterial plasma is considered the gold standard for quantification of [C-11] PBR28 binding to the translocator protein (TSPO), since there is no brain region devoid of TSPO that can serve as reference. The high variability in binding observed using this method has motivated the use of simplified ratio-based approaches such as standardised uptake value ratios (SUVRs) and distribution volume (VT) ratios (DVRs); however, the reliability of these measures and their relationship to VT have not been sufficiently evaluated.Methods: Data from a previously published [C-11] PBR28 test-retest study in 12 healthy subjects were reanalysed. VT was estimated using a two-tissue compartment model. SUVR and DVR values for the frontal cortex were calculated using the whole brain and cerebellum as denominators. Test-retest reliability was assessed for all measures. Interregional correlations were performed for SUV and VT, and principal component analysis (PCA) was applied. Lastly, correlations between ratio-based outcomes and VT were assessed.Results: Reliability was high for VT, moderate to high for SUV and SUVR, and poor for DVR. Very high interregional correlations were observed for both VT and SUV (all R-2 > 85%). The PCA showed that almost all variance (> 98%) was explained by a single component. Ratio-based methods correlated poorly with VT (all R-2 < 34%, divided by genotype).Conclusions: The reliability was good for SUVR, but poor for DVR. Both outcomes showed little to no association with VT, questioning their validity. The high interregional correlations for VT and SUV suggest that after dividing by a denominator region, most of the biologically relevant signal is lost. These observations imply that results from TSPO PET studies using SUVR or DVR estimates should be interpreted with caution.
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| 3. |
- Plaven-Sigray, Pontus, et al.
(författare)
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Accuracy and reliability of [C-11]PBR28 specific binding estimated without the use of a reference region
- 2019
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Ingår i: NeuroImage. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1053-8119 .- 1095-9572. ; 188, s. 102-110
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Tidskriftsartikel (refereegranskat)abstract
- [C-11]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [C-11]PBR28 binding and the most common outcome measure is the total distribution volume (V-T). Notably, V-T reflects both specific binding and non-displaceable binding. Therefore, estimates of specific binding, such as binding potential (e.g. BPND) and specific distribution volume (V-S) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these outcome measures are obtainable for [C-11]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of the non-displaceable distribution volume (V-ND), which can subsequently be used to improve the estimation of BPND and V-S. In this study we evaluated the accuracy of SIME-derived V-ND, and the reliability of resulting estimates of specific binding for [C-11]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments, based on data from 54 unique [C-11]PBR28 examinations, showed that V-ND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge (n = 5) showed that SIME provided V-ND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data (n = 11) showed that SIME-derived V-S values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific binding of [C-11]PBR28, and suggest that V-S can be used in complement to the conventional outcome measure V-T. Additional studies in patient cohorts are warranted.
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| 4. |
- Tuisku, Jouni, et al.
(författare)
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Effects of age, BMI and sex on the glial cell marker TSPO : a multicentre [11C]PBR28 HRRT PET study
- 2019
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 46:11, s. 2329-2338
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [C-11]PBR28. Methods [C-11]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (V-T) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and V-T in the frontal and temporal cortex. BMI showed a significant negative correlation with V-T in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V-T. A subgroup analysis revealed a positive correlation between V-T and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.
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