| 1. |
- Cervenka, Simon, et al.
(författare)
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Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder
- 2012
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Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (behavior). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [C-11]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (Po0.005). Using a repeated measures analysis of covariance, significant effects for time and time x LSAS(anx) change on D2-R-binding potential (BPND) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BPND and LSAS(anx) change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain P<0.05. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD. Translational Psychiatry (2012) 2, e120; doi:10.1038/tp.2012.40; published online 22 May 2012
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| 2. |
- Forsberg, A., et al.
(författare)
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Disease activity in rheumatoid arthritis is inversely related to cerebral TSPO binding assessed by [C-11]PBR28 positron emission tomography
- 2019
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 334
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Tidskriftsartikel (refereegranskat)abstract
- Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [C-11] PBR28. The outcome measure was total distribution volume (V-T) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome V-T or when normalizing V-T to the lateral occipital cortex (p > 0.05). RA patients had numerically lower V-T values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [C-11]PBR28 V-T in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFN gamma and TNF-alpha were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [C-11]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies.
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| 3. |
- Albrecht, Daniel S., et al.
(författare)
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Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation
- 2019
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 75, s. 72-83
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C-11]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C-11]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C-11]PBR28 PET. 11 FM patients and 11 HC were scanned using [C-11]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V-T) were computed from the [C-11]PBR28 data. [C-11]-L-deprenyl-D2 was quantified using lambda k(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C-11]PBR28 ITT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C-11]-L-deprenyl-Ds signal, including those demonstrating elevated [C-11] PBR28 signal in patients (p's >= 0.53, uncorrected). The elevations in [C-11]PBR28 V-T and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C-11] PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C-11]PBR28 signal were not also accompanied by increased [C-11]-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C-11]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.
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| 4. |
- Backman, L, et al.
(författare)
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Age-related cognitive deficits mediated by changes in the striatal dopamine system
- 2000
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Ingår i: AMERICAN JOURNAL OF PSYCHIATRY. - : AMER PSYCHIATRIC PRESS, INC. - 0002-953X. ; 157:4, s. 635-637
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The study examined the influence of losses in dopaminergic function on age-related cognitive deficits. Method: Eleven healthy subjects (21-68 years of age) completed a set of cognitive tasks used to assess perceptual speed and episodic memory.
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| 5. |
- Borg, J., et al.
(författare)
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Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain
- 2016
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Ingår i: Molecular Psychiatry. - London, United Kingdom : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 51, s. 879-879
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Tidskriftsartikel (refereegranskat)abstract
- The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.
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| 6. |
- Cervenka, Simon, et al.
(författare)
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Support for dopaminergic hypoactivity in restless legs syndrome : a PET study on D2-receptor binding
- 2006
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Ingår i: Brain. - Karolinska Univ Hosp Solna, Dept Clin Neurosci, Psychol Sect, Karolinska Inst, SE-17176 Stockholm, Sweden. Karolinska Univ Hosp Huddinge, Div Clin Pharmacol, Dept Lab Med, Stockholm, Sweden. Karolinska Univ Hosp Huddinge, Dept Neurol, Stockholm, Sweden. GlaxoSmithKline Inc, Translat Med & Genet, Cambridge, England. Univ Manchester, Wolfson Mol Imaging Ctr, Manchester, Lancs, England. GlaxoSmithKline Inc, Neurol Discovery Med, Harlow, Essex, England. : OXFORD UNIV PRESS. - 0006-8950 .- 1460-2156. ; 129, s. 2017-2028
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Tidskriftsartikel (refereegranskat)abstract
- Clinical observations support a central role of the dopamine system in restless legs syndrome (RLS) but previous imaging studies of striatal dopamine D2-receptors have yielded inconclusive results. Extrastriatal dopaminergic function has hitherto not been investigated. Sixteen RLS patients naive to dopaminergic drugs and sixteen matched control subjects were examined with PET. [C-11]Raclopride and [C-11]FLB 457 were used to estimate D2-receptor availability in striatum and extrastriatal regions, respectively. Examinations were performed both in the morning (starting between 10:00 and 12:00 h) and evening (starting at 18:00 h). Measures were taken to monitor and control for head movement during data acquisition. In the striatum, patients had significantly higher [C-11]raclopride binding potential (BP) values than controls. In extrastriatal regions, [C-11]FLB 457 BP was higher in patients than controls, and in the regional analysis the difference was statistically significant in subregions of thalamus and the anterior cingulate cortex. The diurnal variability in BP with [C-11]FLB 457 and [C-11]raclopride was within the previously reported test-retest reproducibility for both radioligands. The study supports involvement of the dopamine system in both striatal and extrastriatal brain regions in the pathophysiology of RLS. The brain regions where differences in D2-receptor binding were shown are implicated in the regulation of affective and motivational aspects of sensory processing, suggesting a possible pathway for sensory symptoms in RLS. Increased D2-receptor availability in RLS may correspond to higher receptor densities or lower levels of endogenous dopamine. Both interpretations are consistent with the hypothesis of hypoactive dopaminergic neurotransmission in RLS, as increased receptor levels can be owing to receptor upregulation in response to low levels of endogenous dopamine. The results do not support variations in dopamine D2-receptor availability as a correlate to the diurnal rhythm of RLS symptoms.
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| 7. |
- Collste, K., et al.
(författare)
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Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [C-11]PBR28
- 2017
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Ingår i: Molecular Psychiatry. - : NATURE PUBLISHING GROUP. - 1359-4184 .- 1476-5578. ; 22:6, s. 850-856
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Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [C-11]PBR28. Gray matter (GM) volume of distribution (V-T) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [C-11]PBR28 binding, and gender. There was a significant reduction of [C-11]PBR28 V-T in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM V-T and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.
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| 8. |
- Collste, K., et al.
(författare)
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Test-retest reproducibility of [C-11]PBR28 binding to TSPO in healthy control subjects
- 2016
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 43:1, s. 173-183
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The PET radioligand [C-11]PBR28 binds to the translocator protein (TSPO), a marker of brain immune activation. We examined the reproducibility of [C-11]PBR28 binding in healthy subjects with quantification on a regional and voxel-by-voxel basis. In addition, we performed a preliminary analysis of diurnal changes in TSPO availability. Methods Twelve subjects were examined using a high-resolution research tomograph and [C-11]PBR28, six in the morning and afternoon of the same day, and six in the morning on two separate days. Regional volumes of distribution (V-T) were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. Results For the whole sample, the mean absolute variability in V (T) in the grey matter (GM) was 18.3 +/- 12.7 %. Intraclass correlation coefficients in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 min yielded a variability of 16.9 +/- 14.9 %. There was a strong correlation between the parametric and 2TCM-derived GM values (r=0.99). A significant increase in GM V-T was observed between the morning and afternoon examinations when using secondary methods of quantification (p=0.028). In the subjects examined at the same time of the day, the absolute variability was 15.9 +/- 12.2 % for the 91-min 2TCM data. Conclusion V-T of [C-11]PBR28 binding showed medium reproducibility and high reliability in GM regions. Our findings support the use of parametric approaches for determining [C-11]PBR28 V-T values, and indicate that the acquisition time could be shortened. Diurnal changes in TSPO binding in the brain may be a potential confounder in clinical studies and should be investigated further.
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| 9. |
- Comley, Robert A., et al.
(författare)
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A Comparison of Gray Matter Density in Restless Legs Syndrome Patients and Matched Controls Using Voxel-Based Morphometry
- 2012
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Ingår i: Journal of Neuroimaging. - : WILEY-BLACKWELL. - 1051-2284 .- 1552-6569. ; 22:1, s. 28-32
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Restless legs syndrome (RLS) is a common neurological disorder the pathophysiology of which is incompletely understood. Four studies have examined structural differences between the brains of RLS patients and healthy controls, using voxel-based morphometry (VBM). All 4 studies have provided different results. METHODS Optimized VBM was used to search for structural differences in gray matter density. Sixteen RLS patients naive to dopaminergic drugs and 16 age-and sex-matched controls received structural T1-weighted MR scans. Structural data were analyzed using FSL-VBM. RESULTS No difference in gray matter density was detected between the two groups (voxel-wise significance: no significant voxels at P = .89 (whole brain Family Wise Error (FWE) corrected); no significant voxels at P < .05 (whole brain False Discovery Rate (FDR) corrected; smallest achievable FDR threshold .99). CONCLUSION/DISCUSSION The present study did not replicate (confirm) previous findings of structural brain changes in RLS, but instead supported the findings of a recent study showing a lack of gray matter alteration in an elderly RLS population. More specifically, the results do not support neuronal loss as an underlying disease mechanism in RLS. Potential limitations in the application of VBM are also discussed.
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| 10. |
- Eriksson, Olof, et al.
(författare)
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Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 14960-
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Tidskriftsartikel (refereegranskat)abstract
- The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [68Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [68Ga]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 µg/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [68Ga]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [68Ga]Ga-DO3A-S01-GCG binding in liver. [68Ga]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2 µg/kg. In vivo Kd for [68Ga]Ga-DO3A-S01-GCG corresponded to 0.7 µg/kg, which indicates high potency. The test-retest reproducibility for [68Ga]Ga-DO3A-S01-GCG binding in liver was 5.7 ± 7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5 ± 9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [68Ga]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [68Ga]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.
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