| 1. |
- Matheson, Granville J, et al.
(författare)
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Reliability of volumetric and surface-based normalisation and smoothing techniques for PET analysis of the cortex : A test-retest analysis using [11C]SCH-23390
- 2017
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 155, s. 344-353
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Tidskriftsartikel (refereegranskat)abstract
- Parametric voxelwise analysis is a commonly used tool in neuroimaging, as it allows for identification of regions of effects in the absence of a strong a-priori regional hypothesis by comparing each voxel of the brain independently. Due to the inherent imprecision of single voxel measurements, spatial smoothing is performed to increase the signal-to-noise ratio of single-voxel estimates. In addition, smoothing compensates for imprecisions in anatomical registration, and allows for the use of cluster-based statistical thresholding. Smoothing has traditionally been applied in three dimensions, without taking the tissue types of surrounding voxels into account. This procedure may be suitable for subcortical structures, but is problematic for cortical regions for which grey matter often constitutes only a small proportion of the smoothed signal. New methods have been developed for cortical analysis in which voxels are sampled to a surface, and smoothing is restricted to neighbouring regions along the cortical grey matter in two dimensions. This procedure has recently been shown to decrease intersubject variability and bias of PET data. The aim of this study was to compare the variability, bias and test-retest reliability of volumetric and surface-based methods as they are applied in practice. Fifteen healthy young males were each measured twice using the dopamine D1 receptor radioligand [11C]SCH-23390, and analyses were performed at the level of individual voxels and vertices within the cortex. We found that surface-based methods yielded higher BPND values, lower coefficient of variation, less bias, better reliability and more precise estimates of parametric binding. All in all, these results suggest that surface-based methods exhibit superior performance to volumetric approaches for voxelwise analysis of PET data, and we advocate for their use when a ROI-based analysis is not appropriate.
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| 2. |
- 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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| 3. |
- Plaven-Sigray, Pontus, et al.
(författare)
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Extrastriatal dopamine D2-receptor availability in social anxiety disorder
- 2017
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 27:5, s. 462-469
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in the dopamine system are hypothesized to influence the expression of social anxiety disorder (SAD) symptoms. However, molecular imaging studies comparing dopamine function between patients and control subjects have yielded conflicting results. Importantly, while all previous investigations focused on the striatum, findings from activation and blood flow studies indicate that prefrontal and limbic brain regions have a central role in the pathophysiology. The objective of this study was to investigate extrastriatal dopamine D2-receptor (D2-R) availability in SAD. We examined 12 SAD patients and 16 healthy controls using positron emission tomography and the high-affinity D2-R radioligand [C-11]FLB457. Parametric images of D2-R binding potential were derived using the Logan graphical method with cerebellum as reference region. Two-tailed one-way independent ANCOVAs, with age as covariate, were used to examine differences in D2-R availability between groups using both region-based and voxel-wise analyses. The region-based analysis showed a medium effect size of higher D2-R levels in the orbitofrontal cortex (OFC) in patients, although this result did not remain significant after correction for multiple comparisons. The voxel-wise comparison revealed elevated D2-R availability in patients within OFC and right dorsolateral prefrontal cortex after correction for multiple comparisons. These preliminary results suggest that an aberrant extrastriatal dopamine system may be part of the disease mechanism in SAD.
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| 4. |
- Plaven-Sigray, Pontus, et al.
(författare)
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Is dopamine D1 receptor availability related to social behavior? : A positron emission tomography replication study
- 2018
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- Background Associations between dopamine receptor levels and pro- and antisocial behavior have previously been demonstrated in human subjects using positron emission tomography (PET) and self-rated measures of personality traits. So far, only one study has focused on the dopamine D1-receptor (D-1-R), finding a positive correlation with the trait social desirability, which is characterized by low dominant and high affiliative behavior, while physical aggression showed a negative correlation. The aim of the present study was to replicate these previous findings using a new independent sample of subjects.Materials and methods Twenty-six healthy males were examined with the radioligand [C-11]SCH-23390, and completed the Swedish universities Scales of Personality (SSP) which includes measures of social desirability and physical trait aggression. The simplified reference tissue model with cerebellum as reference region was used to calculate BPND values in the whole striatum and limbic striatum. The two regions were selected since they showed strong association between D-I-R availability and personality scores in the previous study. Pearson's correlation coefficients and replication Bayes factors were then employed to assess the replicability and robustness of previous results.Results There were no significant correlations (all p values >0.3) between regional BPND values and personality scale scores. Replication Bayes factors showed strong to moderate evidence in favor no relationship between Dl-receptor availability and social desirability (striatum BF01 = 12.4; limbic striatum BF01 = 7.2) or physical aggression scale scores (limbic striatum BF01 = 3.3), compared to the original correlations.Discussion We could not replicate the previous findings of associations between D1-R availability and either pro- or antisocial behavior as measured using the SSP. Rather, there was evidence in favor of failed replications of associations between BPND and scale scores. Potential reasons for these results are restrictive variance in both PET and personality outcomes due to high sample homogeneity, or that the previous findings were false positives.
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| 5. |
- Plavén-Sigray, Pontus, et al.
(författare)
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Thalamic dopamine D2-receptor availability in schizophrenia : a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis.
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 27:2, s. 1233-1240
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [11C]FLB457. The main outcome was D2-R binding potential (BPND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen's dz = -0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BPND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen's dz = -0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen's d = -0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.
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| 6. |
- Stenkrona, Per, et al.
(författare)
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[11C]SCH23390 binding to the D-1-dopamine receptor in the human brain : a comparison of manual and automated methods for image analysis
- 2018
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Ingår i: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: The D-1-dopamine receptor radioligand [C-11] SCH23390 has been frequently used in PET studies. In drug-naive patients with schizophrenia, the findings have been inconsistent, with decreases, increases, and no change in the frontal cortex D-1-dopamine receptors. While these discrepancies are likely primarily due to a lack of statistical power in these studies, we speculated that an additional explanation may be the differences due to methods of image analysis between studies, affecting reliability as well as bias between groups. Methods: Fifteen healthy subjects underwent two PET measurements with [C-11] SCH23390 on the same day. The binding potential (BPND) was compared using a 95% confidence interval following manual and automated delineation of a region of interest (ROI) as well as with and without frame-by-frame realignment. Results: Automated target region delineation produced lower BPND values, while automated delineation of the reference region yielded higher BPND values. However, no significant differences were observed for repeatability using automated and manual delineation methods. Frame-by-frame realignment generated higher BPND values and improved repeatability. Conclusions: The results suggest that the choice of ROI delineation method is not an important factor for reliability, whereas the improved results following movement correction confirm its importance in PET image analysis. Realignment is therefore especially important for measurements in patient populations such as schizophrenia or Parkinson's disease, where motion artifacts may be more prevalent.
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| 7. |
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| 8. |
- Svensson, Jonas E., et al.
(författare)
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Serotonin transporter availability increases in patients recovering from a depressive episode
- 2021
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Ingår i: Translational Psychiatry. - : Springer. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Molecular imaging studies have shown low cerebral concentration of serotonin transporter in patients suffering from depression, compared to healthy control subjects. Whether or not this difference also is present before disease onset and after remission (i.e. a trait), or only at the time of the depressive episode (i.e. a state) remains to be explored. We examined 17 patients with major depressive disorder with positron emission tomography using [C-11]MADAM, a radioligand that binds to the serotonin transporter, before and after treatment with internet-based cognitive behavioral therapy. In all, 17 matched healthy control subjects were examined once. Cerebellum was used as reference to calculate the binding potential. Differences before and after treatment, as well as between patients and controls, were assessed in a composite cerebral region and in the median raphe nuclei. All image analyses and confirmatory statistical tests were preregistered. Depression severity decreased following treatment (p<0.001). [C-11]MADAM binding in patients increased in the composite region after treatment (p=0.01), while no change was observed in the median raphe (p=0.51). No significant difference between patients at baseline and healthy controls were observed in the composite region (p=0.97) or the median raphe (p=0.95). Our main finding was that patients suffering from a depressive episode show an overall increase in cerebral serotonin transporter availability as symptoms are alleviated. Our results suggest that previously reported cross-sectional molecular imaging findings of the serotonin transporter in depression most likely reflect the depressive state, rather than a permanent trait. The finding adds new information on the pathophysiology of major depressive disorder.
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| 9. |
- Svensson, Jonas E., et al.
(författare)
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Validity and reliability of extrastriatal [C-11]raclopride binding quantification in the living human brain
- 2019
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Ingår i: NeuroImage. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1053-8119 .- 1095-9572. ; 202
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Tidskriftsartikel (refereegranskat)abstract
- [C-11]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [C-11]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [C-11]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [C-11]raclopride: (i) To assess the validity of extrastriatal [C-11]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. (ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model with cerebellum as reference. Quetiapine dosing was associated with decrease in [C-11]raclopride BPND in temporal cortex (18 +/- 17% occupancy) and thalamus (20 +/- 17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51 +/- 4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [C-11]raclopride PET, quantified using cerebellum as reference, is not a suitable tool to measure D2/3R in extrastriatal regions.
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| 10. |
- 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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