| 1. |
- Cervenka, Simon, et al.
(författare)
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Associations between dopamine D2-receptor binding and cognitive performance indicate functional compartmentalization of the human striatum
- 2008
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Ingår i: NeuroImage. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1053-8119 .- 1095-9572. ; 40:3, s. 1287-1295
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Tidskriftsartikel (refereegranskat)abstract
- Based on pharmacological, neuroanatomical, and lesion studies in animals, a functional compartmentalization of the striatal complex has been proposed. However, this has not been convincingly demonstrated in human subjects. Most functions ascribed to the striatum have been linked to its dense dopaminergic innervation, from motor control to higher-order brain functions ( e. g., cognition), making the dopamine system a suitable probe for striatal function. Limbic striatum, a region involved in reward processing, has recently been implicated also in episodic memory function. Here we examined striatal dopamine D2-receptor binding in 16 healthy subjects using PET and the radioligand [C-11] raclopride, in relation to cognitive performance. Receptor availability in limbic striatum was related to performance in tests of episodic memory, but not to tests of verbal fluency and general knowledge. By contrast, D2 binding in associative and sensorimotor striatum was less strongly related to episodic memory, but showed associations to the non-episodic tasks. These findings provide biochemical evidence for a functional compartmentalization of human striatum, and serve as a starting point for a more detailed investigation of striatal biomarkers in the normal brain as well as in neurodegenerative disorders. (c) 2008 Elsevier Inc. All rights reserved.
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| 2. |
- 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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| 3. |
- Cselenyi, Zsolt, et al.
(författare)
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[C-11]PBB3 binding in A beta(-) or A beta(+) corticobasal syndrome
- 2023
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Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 77:4
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Tidskriftsartikel (refereegranskat)abstract
- Corticobasal syndrome (CBS) is associated with 4-repeat tauopathy and/or Alzheimers disease pathologies. To examine tau and amyloid-beta (A beta) deposits in CBS patients using positron emission tomography (PET). Eight CBS patients and three healthy individuals lacking amyloid pathology underwent PET with [C-11]PBB3 for tau imaging, and [C-11]AZD2184 for A beta. Subcortical and cortical binding of [C-11]PBB3 was compared between A beta(-) and A beta(+) CBS patients and reference group. Postmortem analysis was done in one CBS patient. Three CBS patients were considered A beta(+). Total binding was higher in all patients compared to the reference group. Similar regional binding profiles of [C-11]PBB3 in A beta(+) and A beta(-) CBS patients were found. Elevated [C-11]PBB3 binding in pallidum was observed in all CBS patients. Cortical [C-11]PBB3 binding was higher in A beta(+) compared to A beta(-) patients. Postmortem analysis of a CBS patient revealed corticobasal degeneration neuropathology and [C-11]PBB3 autofluorescence in some tau-positive structures. [C-11]PBB3 is elevated in CBS patients with binding in relevant areas capturing some, but not all, 4-repeat tauopathy in CBS.
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| 4. |
- Cselényi, Zsolt
(författare)
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Development, validation and application of advanced neuroimaging analysis tools for in vivo neuroreceptor studies
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Positron emission tomography (PET) is an imaging technology, which can be used to study neuroreceptors in the human brain in vivo. The technique estimates the regional binding of radiolabelled ligands to neuroreceptors and the data are commonly displayed as images showing the distribution of radioactivity in the brain volume. A traditional image analysis approach builds upon reduction of noise in a region of interest (ROI) by averaging radioactivity in the volume elements (voxels) of the ROI. This approach is efficient to improve the reliability of the time curves but does not allow for a detailed analysis of the entire brain. To obtain detailed three-dimensional maps of binding parameters in brain, novel approaches have been developed during recent years. The aim of the present thesis project is to examine and validate the repertoire of advanced computerised tools used to obtain parametric maps of receptor binding in basic and clinical neuroscience research. In addition, the increasing number of suitable PET radioligands, targeted for different neuroreceptor systems, calls for approaches that allow for a combined analysis of multiple receptor systems. A parametric mapping approach using wavelet filtering was evaluated in a cross-validation design. Data from PET-studies on regional D2/D3 dopamine and 5-HT1A serotonin receptor binding in the human brain were used to compare the binding potential (BP) estimates of the wavelet-based approach and other parametric imaging approaches to the ROI-based graphical Logan analysis which was used as a reference. The approach using three-dimensional wavelet filtering was noise-tolerant and yielded BP maps with regional averages closely matching the reference values. Overall, the wavelet-based approach seemed to provide the most valid and reliable estimates across regions with a wide range of receptor densities. However, there was some loss of resolution, which may be critical for analysis of binding in small anatomical regions. Another set of parametric mapping approaches is similar to the ROI-based analyses in the sense that signal averaging is used to reduce noise. However, these approaches do not average the time-activity curves (TAC s) of spatially adjacent voxels but that of voxels having a TAC with a similar shape. A process was developed to classify voxels into a large number of groups (clusters) and thus to obtain an average TAC for voxels with a similar TAC. The classification was performed using an artificial neural network model, called the 'growing adaptive neural gas' (GANG), which was developed as part of the thesis. Parameter estimation was performed on the average TAC s and the parameters were then back-projected to the original spatial locations of the voxels thereby providing 3D parametric maps. The approach was applied to PET images measuring D2/D3 receptor binding. The results indicate that the approach can be used to effectively reduce noise. The created parametric maps were highly detailed and the binding distribution was consistent with parametric images obtained with previous approaches. Novel technical approaches are required in combined analyses of multiple neuroreceptor systems. Such approaches have to be capable of operating on very large parametric image datasets. An initial step is the development of exploratory data-mining tools, which provide guidance as to the structure of complex multi-individual, multi-receptor datasets. For this task, an unsupervised and unbiased data-mining tool was developed and proposed. The tool includes a GANG-based clustering of multi-receptor data. The proposed approach was tested on a dataset containing BP maps of the serotonin transporter and the 5-HT1A receptors obtained in the same individuals. The outputs of the method were multi-receptor maps with potential to reveal complex relationships and tendencies in a dataset with several ligands. Such maps may have value in clinical research on multi-receptor interactions and pattern changes in the human brain. In conclusion, the present thesis has examined and extended a methodological platform that allows for additional gain of information from routinely generated data in PET studies on neuroreceptor binding. The results support application of parametric image analysis in basic and clinical research.
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| 5. |
- Forsberg, Anton, et al.
(författare)
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Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients
- 2013
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer-Verlag New York. - 1619-7070 .- 1619-7089. ; 40:4, s. 580-593
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD).METHODS: In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.RESULTS: AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.CONCLUSION: Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
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| 6. |
- Kågedal, Matts, et al.
(författare)
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A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region
- 2013
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 82, s. 160-169
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Tidskriftsartikel (refereegranskat)abstract
- AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [C-11]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived fro m each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.
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| 7. |
- Kågedal, Matts, et al.
(författare)
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Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers
- 2012
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 61:4, s. 849-856
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to develop a model simultaneously estimating (11)C-AZD9272 radioligand kinetics and the relationship between plasma concentration of AZD9272 and receptor occupancy in the human brain.AZD9272 is a new chemical entity pharmacologically characterised as a noncompetitive antagonist at the metabotropic glutamate receptor subtype 5 (mGluR5). Positron emission tomography (PET) was used to measure the time course of ((11)C-AZD9272) in the brain. The study included PET measurements in six healthy volunteers where the radioligand was given as a tracer dose alone as well as post oral treatment with different doses of unlabelled AZD9272. Estimation of radioligand kinetics, including saturation of receptor binding was performed by use of non-linear mixed effects modelling. Data from the regions with the highest (ventral striatum) and lowest (cerebellum) radioligand concentrations were included in the analysis. It was assumed that the extent of non-displaceable brain uptake was the same in both regions while the rate of CNS uptake and the receptor density differed.The results of the analysis showed that AZD9272 binding at the receptor is saturable with an estimated plasma concentration corresponding to 50% occupancy of approximately 200nM. The density of the receptor binding sites was estimated to 800nM and 200nM in ventral striatum and cerebellum respectively. By simultaneously analysing data from several PET measurements and different brain regions in a non-linear mixed effects framework it was possible to estimate parameters of interest that would otherwise be difficult to quantify.
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| 8. |
- Matheson, Granville J., et al.
(författare)
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Diurnal and seasonal variation of the brain serotonin system in healthy male subjects
- 2015
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Ingår i: NeuroImage. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1053-8119 .- 1095-9572. ; 112, s. 225-231
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Tidskriftsartikel (refereegranskat)abstract
- The mammalian circadian clock underlies both diurnal and seasonal changes in physiology, and its function is thought to be disturbed in both seasonal and non-seasonal depression. In humans, molecular imaging studies have reported seasonal changes in the serotonin system. Despite the role of the circadian clock in generating seasonal physiological changes, however, diurnal variation of serotonin receptors and transporters has never been directly studied in humans. We used positron emission tomography to examine diurnal and seasonal changes in the serotonin 5-HT1A receptor and serotonin transporter in two large cohorts of healthy male subjects, employing a cross-sectional design. In 56 subjects measured with [C-11] WAY-100635, we observed diurnal increases in the availability of 5-HT1A receptors in the cortex. In 40 subjects measured with [C-11] MADAM, a decrease in 5-HTT was observed in the midbrain across the day. We also found seasonal changes in the 5-HT1A receptor in serotonin projection regions, with higher availability on days with a longer duration of daylight. Our observation that serotonin receptor and transporter levels may change across the day in humans is corroborated by experimental research in rodents. These findings have important implications for understanding the relationship between the circadian and serotonin systems in both the healthy brain and in affective disorders, as well as for the design of future molecular imaging studies. (C) 2015 Elsevier Inc. All rights reserved.
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| 9. |
- 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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| 10. |
- Mattsson, Patrik, et al.
(författare)
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High Contrast PET Imaging of Subcortical and Allocortical Amyloid-β in Early Alzheimer's Disease Using [11C]AZD2184
- 2024
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 98:4, s. 1391-1401
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Deposits of amyloid-β (Aβ) appear early in Alzheimer's disease (AD).OBJECTIVE: The aim of the present study was to compare the presence of cortical and subcortical Aβ in early AD using positron emission tomography (PET).METHODS: Eight cognitively unimpaired (CU) subjects, 8 with mild cognitive impairment (MCI) and 8 with mild AD were examined with PET and [11C]AZD2184. A data driven cut-point for Aβ positivity was defined by Gaussian mixture model of isocortex binding potential (BPND) values.RESULTS: Sixteen subjects (3 CU, 5 MCI and 8 AD) were Aβ-positive. BPND was lower in subcortical and allocortical regions compared to isocortex. Fifteen of the 16 Aβ-positive subjects displayed Aβ binding in striatum, 14 in thalamus and 10 in allocortical regions.CONCLUSIONS: Aβ deposits appear to be widespread in early AD. It cannot be excluded that deposits appear simultaneously throughout the whole brain which has implications for improved diagnostics and disease monitoring.
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