1. |
- Bjerkenstedt, Lars, et al.
(författare)
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Support for limited brain availability of tyrosine in patients with schizophrenia
- 2006
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Ingår i: International Journal of Neuropsychopharmacology. - 1461-1457 .- 1469-5111. ; 9, s. 247-255
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Tidskriftsartikel (refereegranskat)abstract
- Several mechanisms have been suggested to account for altered dopaminergic neurotransmission in schizophrenia. The brain is the only organ for which amino-acid transport is limited and competition for transport over the blood-brain barrier (BBB) occurs at physiological plasma concentrations. One line of research suggests that patients with schizophrenia have altered brain levels of the essential amino acid tyrosine, the precursor for the synthesis of dopamine. The most common hypothesis is that less tyrosine is available because of competition with elevated levels of other amino acids. By consequence, the synthesis of dopamine in the brain will decrease. In contrast, another line of evidence suggests a change in the affinity for one of the transport proteins. A limitation of this research has been that the systems for amino-acid transport across the BBB have not been fully characterized at a molecular or functional level. The L system is the major system for transport of tyrosine across cell membranes including the BBB. The A system is also involved in this transport. Earlier in-vitro studies using fibroblasts have demonstrated a normal L system in schizophrenia but nevertheless reduced tyrosine transport. The combination of molecular research, fibroblast techniques, and brain imaging provides a new basis for clinical research on the role of amino-acid membrane transport in schizophrenia.
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2. |
- Bäckman, Lars, et al.
(författare)
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Dopamine and cognitive aging : a strong relationship
- 2006
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Ingår i: Progress in psychological science around the world. Volume 1 neural, cognitive and developmental issues. - : Psychology Press. - 9780203783122 - 9781841699615 - 9781138883314 ; , s. 455-469
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Konferensbidrag (refereegranskat)
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3. |
- Bäckman, Lars, et al.
(författare)
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Dopamine D(1) receptors and age differences in brain activation during working memory
- 2011
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Ingår i: Neurobiology of Aging. - Fayetteville, N.Y : Elsevier. - 0197-4580 .- 1558-1497. ; 32:10, s. 1849-1856
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Tidskriftsartikel (refereegranskat)abstract
- In an fMRI study, 20 younger and 20 healthy older adults were scanned while performing a spatial working-memory task under two levels of load. On a separate occasion, the same subjects underwent PET measurements using the radioligand [(11)C] SCH23390 to determine dopamine D(1) receptor binding potential (BP) in caudate nucleus and dorsolateral prefrontal cortex (DLPFC). The fMRI study revealed a significant load modulation of brain activity (higher load>lower load) in frontal and parietal regions for younger, but not older, adults. The PET measurements showed marked age-related reductions of D(1) BP in caudate and DLPFC. Statistical control of caudate and DLPFC D(1) binding eliminated the age-related reduction in load-dependent BOLD signal in left frontal cortex, and attenuated greatly the reduction in right frontal and left parietal cortex. These findings suggest that age-related alterations in dopaminergic neurotransmission may contribute to underrecruitment of task-relevant brain regions during working-memory performance in old age.
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4. |
- Bäckman, Lars, et al.
(författare)
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The correlative triad among aging, dopamine, and cognition : current status and future prospects.
- 2006
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Ingår i: Neuroscience and Biobehavioral Review. - : Elsevier BV. - 0149-7634. ; 30:6, s. 791-807
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The brain neuronal systems defined by the neurotransmitter dopamine (DA) have since long a recognized role in the regulation of motor functions. More recently, converging evidence from patient studies, animal research, pharmacological intervention, and molecular genetics indicates that DA is critically implicated also in higher-order cognitive functioning. Many cognitive functions and multiple markers of striatal and extrastriatal DA systems decline across adulthood and aging. Research examining the correlative triad among adult age, DA, and cognition has found strong support for the view that age-related DA losses are associated with age-related cognitive deficits. Future research strategies for examining the DA-cognitive aging link include assessing (a) the generality/specificity of the effects; (b) the relationship between neuromodulation and functional brain activation; and (c) the release of DA during actual task performance.
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5. |
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6. |
- Karlsson, Sari, et al.
(författare)
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Modulation of striatal dopamine D1 binding by cognitive processing
- 2009
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Ingår i: NeuroImage. - : Elsevier. - 1053-8119 .- 1095-9572. ; 48:2, s. 398-404
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Tidskriftsartikel (refereegranskat)abstract
- There is strong evidence that dopamine (DA) is implicated in higher-order cognitive functioning, but it remains controversial whether D1 receptor binding can be modified by cognitive activity. We examined striatal D1 binding potential (BP) in 20 younger (22-30 years) and 20 older (65-75 years) persons who underwent two [(11)C] SCH 23390 PET measurements, one while resting and one while performing a cognitive task taxing inhibitory functioning. The younger persons showed significant task-related BP reductions in sensorimotor, limbic, and associative striatum during cognitive activity compared to rest. Older persons showed no reliable BP reductions in any striatal subregion. These findings demonstrate that D1 receptor binding can be modified by cognitive activity in younger persons, but also provide novel evidence for the notion that human aging is associated not only with lower DA receptor density but also with altered modifiability of the DA system.
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7. |
- Karlsson, Sari, et al.
(författare)
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Relationship of dopamine D1 receptor binding in striatal and extrastriatal regions to cognitive functioning in healthy humans
- 2011
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Ingår i: NeuroImage. - : Elsevier. - 1053-8119 .- 1095-9572. ; 57:2, s. 346-351
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Tidskriftsartikel (refereegranskat)abstract
- Dopamine (DA) availability in both striatal and extrastriatal brain regions has been implicated in cognitive performance. Given that different brain regions are neuroanatomically and functionally different, DA receptor binding in different brain regions may be selectively important to specific cognitive functions. Using PET and the radioligand SCH23390, we measured D1 receptor binding potential (BP(ND)) in dorsolateral prefrontal cortex (DLPFC), hippocampus (HC), as well as in sensorimotor (SMST), associative (AST), and limbic (LST) striatum in 20 healthy younger persons. Subjects completed tasks assessing executive functioning, episodic memory, speed, and general knowledge. Unlike previous reports, we found no linear or curvilinear relationships between D1 receptor binding in DLPFC and performance in any cognitive task. However, BP(ND) in HC was positively linked to executive performance as well as to speed and knowledge. With regard to the striatal subregions, D1 BP(ND) in SMST was more strongly related to speed compared to the other striatal subregions, whereas D1 BP(ND) in AST was more strongly linked to general knowledge. These findings provide support for the notion that D1 receptors in separate brain regions are differentially related to performance in tasks tapping various cognitive domains.
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8. |
- Kaufmann, Tobias, et al.
(författare)
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Common brain disorders are associated with heritable patterns of apparent aging of the brain
- 2019
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 22:10, s. 1617-
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Tidskriftsartikel (refereegranskat)abstract
- Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.
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9. |
- MacDonald, Stuart W S, et al.
(författare)
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Extrastriatal dopamine D2 receptor binding modulates intraindividual variability in episodic recognition and executive functioning.
- 2009
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Ingår i: Neuropsychologia. - : Elsevier BV. - 0028-3932 .- 1873-3514. ; 47:11, s. 2299-2304
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Tidskriftsartikel (refereegranskat)abstract
- Intraindividual variability (IIV) reflects lawful but transient within-person changes in performance. Increased IIV in cognition shares systematic associations with numerous conditions characterized by alterations in dopamine (DA) neuromodulation (e.g., old age, ADHD, schizophrenia, and Parkinson's disease). In a group of normal middle-aged adults, we examined links between PET-derived measures of D2 receptor binding in striatum, orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and hippocampus (HC) and IIV for tasks assessing recognition memory and executive functioning. An index of IIV, the intraindividual standard deviation (ISD), was computed across successful response latency trials for each cognitive outcome. Lower D2 binding in OC, ACC, and HC, but not striatum, was associated with increasing ISDs for the memory and executive measures. Consistent with neurocomputational models, the present findings suggest a role for extrastriatal DA neurotransmission in modulating variability in cognitive functioning.
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10. |
- Mattsson, Patrik, et al.
(författare)
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β-Amyloid binding in elderly subjects with declining or stable episodic memory function measured with PET and [11C]AZD2184
- 2015
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 42:10, s. 1507-1511
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cognitive decline has been suggested as an early marker for later onset of Alzheimer's disease. We therefore explored the relationship between decline in episodic memory and β-amyloid using positron emission tomography (PET) and [11C]AZD2184, a radioligand with potential to detect low levels of amyloid deposits.Methods: Healthy elderly subjects with declining (n = 10) or stable (n = 10) episodic memory over 15 years were recruited from the population-based Betula study and examined with PET. Brain radioactivity was measured after intravenous administration of [11C]AZD2184 The binding potential BP ND was calculated using linear graphical analysis with the cerebellum as reference region.Results: The binding of [11C]AZD2184 in total grey matter was generally low in the declining group, whereas some binding could be observed in the stable group. Mean BP ND was significantly higher in the stable group compared to the declining group (p = 0.019). An observation was that the three subjects with the highest BPND were ApoE ε4 allele carriers.Conclusions: We conclude that cognitive decline in the general population does not seem to stand by itself as an early predictor for amyloid deposits.
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11. |
- Plaven-Sigray, Pontus, et al.
(författare)
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Dopamine D1 receptor availability is related to social behavior : A positron emission tomography study
- 2014
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 102, s. 590-595
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Tidskriftsartikel (refereegranskat)abstract
- Dysfunctional interpersonal behavior is thought to underlie a wide spectrum of psychiatric disorders; however, the neurobiological underpinnings of these behavioral disturbances are poorly understood. Previous molecular imaging studies have shown associations between striatal dopamine (DA) D2-receptor binding and interpersonal traits, such as social conformity. The objective of this study was to explore, for the first time, the role of DA D1-receptors (D1-Rs) in human interpersonal behavior. Twenty-three healthy subjects were examined using positron emission tomography and the radioligand [C-11] SCH23390, yielding D1-R binding potential values. Striatal D1-R binding was related to personality scales selected to specifically assess one dimension of interpersonal behavior, namely a combination of affiliation and dominance (i.e., the Social Desirability, Verbal Trait Aggression and Physical Trait Aggression scales from Swedish Universities Scales of Personality). An exploratory analysis was also performed for extrastriatal brain regions. D1-R binding potential values in the limbic striatum(r= .52; p= .015), associative striatum(r= .55; p= .009), and sensorimotor striatum(r= .67; p= .001) were positively related to Social Desirability scores. D1-R binding potential in the limbic striatum (r= -.51; p = .019) was negatively associated with Physical Trait Aggression scores. For extrastriatal regions, Social Desirability scores showed positive correlations in the amygdala (r = .60; p = .006) and medial frontal cortex (r= .60; p = .004). This study provides further support for the role of DA function in the expression of disaffiliative and dominant traits. Specifically, D1-R availability may serve as a marker for interpersonal behavior in humans. Associations were demonstrated for the same dimension of interpersonal behavior as for D2-R, but in the opposite direction, suggesting that the two receptor subtypes are involved in the same behavioral processes, but with different functional roles.
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12. |
- Rieckmann, Anna, et al.
(författare)
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Dopamine D1 Receptor Associations within and between Dopaminergic Pathways in Younger and Elderly Adults : Links to Cognitive Performance
- 2011
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Ingår i: Cerebral Cortex. - Oxford : Oxford University Press. - 1047-3211 .- 1460-2199. ; 21:9, s. 2023-2032
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Tidskriftsartikel (refereegranskat)abstract
- Age-related dopamine (DA) losses have been extensively demonstrated for the D2 receptor subtype. Comparatively little is known about adult age changes regarding D1 receptors. In this study, we demonstrate marked age-related D1 receptor losses in striatal, limbic, and cortical areas using positron emission tomography and the radioligand [11C]SCH23390 in humans. Interregional correlations of binding potential (BP) values were high for areas within DA pathways in younger and elderly adults alike. Furthermore, interregional correlations in D1 BP between DA pathways were uniformly high in younger adults, indicating that D1 receptor densities in striatal, limbic, and cortical areas are not regulated independently, despite dopaminergic innervation from different midbrain areas. For elderly adults, between-pathway correlations of D1 receptor densities were preserved only between mesolimbic and mesocortical areas, whereas striatal BPs were weakly related to those in limbic and neocortical regions. Importantly, weak between-pathway correlations in elderly adults were found only for the slower half of the sample when BP was estimated during a cognitive interference task. These results suggest that D1 receptor densities in different pathways are not regulated independently in younger adults, but segregate in older age, and that this segregation of D1 receptor systems may be related to age-related cognitive slowing.
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13. |
- Alnaes, Dag, et al.
(författare)
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Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk
- 2019
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Ingår i: JAMA psychiatry. - : AMER MEDICAL ASSOC. - 2168-6238 .- 2168-622X. ; 76:7, s. 739-748
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Tidskriftsartikel (refereegranskat)abstract
- ImportanceBetween-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. ObjectivesTo compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and ParticipantsThis case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and MeasuresMean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. ResultsA comparison of 1151 patients with schizophrenia (mean [SD] age,33.8[10.6] years; 68.6% male [n=790] and 31.4% female [n=361]) with 2010 healthy controls (mean [SD] age,32.6[10.4] years; 56.0% male [n=1126] and 44.0% female [n=884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t=3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age,55.9 [7.5] years; 48.2% male [n=6025] and 51.8% female [n=6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t=-3.00) but was not significantly associated with dispersion. Conclusions and RelevanceThis study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.
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14. |
- 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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15. |
- Jahan, Mahabuba, et al.
(författare)
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The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass.
- 2018
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand.METHODS: The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments.RESULTS: The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy.CONCLUSION: We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.
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16. |
- 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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17. |
- Varrone, Andrea, et al.
(författare)
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5-HT1B receptor imaging and cognition : A positron emission tomography study in control subjects and parkinson's disease patients
- 2015
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Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 69:7, s. 365-374
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThe serotonin 5-HT1B receptor subtype is involved in the modulation of serotonin release and is a target of interest for neuroreceptor imaging. Previous studies have shown that the serotonin system is affected in Parkinson's disease (PD). Cognitive function, frequently impaired in PD, has been linked to the serotonin system. The aim of this study was to examine whether 5-HT1B receptor availability in the brain of healthy subjects and PD patients is associated with measures of cognitive function. MethodsTwelve control subjects and ten PD patients with normal mini-mental state examination scores were included in this study. Cognitive function was evaluated by assessment of semantic, episodic, and working memory, as well as fluency and visual attention. Creative ability, a measure of divergent thinking, was examined with the alternative uses of objects task. PET measurements were performed with the 5-HT1B receptor-radioligand [C-11]AZ10419369 using the HRRT system. ResultsPD patients showed statistically significant lower measures of semantic and episodic memory, as well as creative ability, compared with control subjects. Statistically significant positive correlations were found in control subjects between creative ability and average 5-HT1B receptor availability in grey matter, and in PD patients between scores of Beck Depression Inventory-II and creative ability. ConclusionThough creativity has been conventionally linked to dopamine function, our findings in control subjects suggest a link between 5-HT1B receptor availability and creative ability. In PD patients, creative ability was significantly associated with depressive symptoms but not with 5-HT1B receptor availability. This finding deserves further investigation in future studies.
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18. |
- Varrone, Andrea, et al.
(författare)
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Positron emission tomography imaging of 5-hydroxytryptamine(1B) receptors in Parkinson's disease
- 2014
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 35:4, s. 867-875
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Tidskriftsartikel (refereegranskat)abstract
- Impairment of the central serotonin system in Parkinson's disease (PD) has been shown postmortem and in vivo with positron emission tomography (PET). The aim of this PET study was to examine and compare the availability of the 5-hydroxytryptamine (5-HT)(1B)-receptor subtype in patients with PD and age-matched control subjects. Twelve control subjects and 12 PD patients were examined with PET using the 5-HT1B-radioligand [C-11]AZ10419369. In PD patients, 5-HT1B-receptor availability in the right orbitofrontal cortex was lower than in control subjects. A statistically significant negative correlation between 5-HT1B-receptor availability and age was obtained for the right temporal cortex in control subjects and for the right midbrain and left parahippocampal gyrus in PD patients. The lower regional 5-HT1B-receptor availability is in line with previous studies showing a decrease of serotonin imaging markers in PD and corroborates a role of the serotonin system in the pathophysiology of PD. The demonstrated age effect on 5-HT1B receptors suggest a physiologic and PD-related decline of serotonin function, indicating the importance of controlling for age in clinical studies.
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19. |
- Benlloch, Jose M., et al.
(författare)
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The MINDVIEW project : First results
- 2018
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Ingår i: European psychiatry. - : Cambridge University Press (CUP). - 0924-9338 .- 1778-3585. ; 50, s. 21-27
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Tidskriftsartikel (refereegranskat)abstract
- We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from 11C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that 11C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naïve, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia.
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20. |
- Borg, Jacqueline, et al.
(författare)
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The serotonin system and spiritual experiences
- 2003
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 160:11, s. 1965-1969
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The serotonin system has long been of interest in biological models of human personality. The purpose of this positron emission tomography (PET) study was to search for relationships between serotonin 5-HT(1A) receptor density and personality traits. METHOD: Fifteen normal male subjects, ages 20-45 years, were examined with PET and the radioligand [(11)C]WAY100635. Personality traits were assessed with the Swedish version of the Temperament and Character Inventory self-report questionnaire. Binding potential, an index for the density of available 5-HT(1A) receptors, was calculated for the dorsal raphe nuclei, the hippocampal formation, and the neocortex. For each region, correlation coefficients between 5-HT(1A) receptor binding potential and Temperament and Character Inventory personality dimensions were calculated and analyzed in two-tailed tests for significance. RESULTS: The authors found that the binding potential correlated inversely with scores for self-transcendence, a personality trait covering religious behavior and attitudes. No correlations were found for any of the other six Temperament and Character Inventory dimensions. The self-transcendence dimension consists of three distinct subscales, and further analysis showed that the subscale for spiritual acceptance correlated significantly with binding potential but not with the other two subscales. CONCLUSIONS: This finding in normal male subjects indicated that the serotonin system may serve as a biological basis for spiritual experiences. The authors speculated that the several-fold variability in 5-HT(1A) receptor density may explain why people vary greatly in spiritual zeal.
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21. |
- Borg,, et al.
(författare)
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Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans.
- 2009
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Ingår i: The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). - 1461-1457. ; 12:6, s. 783-792
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Tidskriftsartikel (refereegranskat)abstract
- The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.
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22. |
- Cervenka, Simon, et al.
(författare)
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Age-related diurnal effect on D-2 receptor binding : a preliminary PET study
- 2008
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Ingår i: International Journal of Neuropsychopharmacology. - : OXFORD UNIV PRESS. - 1461-1457 .- 1469-5111. ; 11:5, s. 671-678
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Tidskriftsartikel (refereegranskat)abstract
- Animal research has shown a diurnal variation in dopamine neurotransmission, with a reduced release at night. Variations in biomarkers for the dopamine system over the day have, however, not been investigated in human subjects. In this preliminary PET study, we used the radioligands [C-11]raclopride and [C-11]FLB457 to determine dopamine D-2-receptor binding in 16 human subjects in the morning and evening on the same day. The average difference between morning and evening examinations did not indicate a diurnal effect on D-2 receptor availability. However, when age was taken into account in the analysis, a pattern emerged where individuals in the lower age range showed reduced evening binding while in older subjects binding potential increased. The product-moment correlation between morning-evening change and age was statistically significant in insula, medial frontal cortex and rostral anterior cingulate. The findings, if replicated, have direct relevance for applied PET studies and could also prove relevant with regard to age effects on dopamine-related behaviour such as arousal and cognitive performance.
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23. |
- Cervenka, Simon, et al.
(författare)
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Association between striatal and extrastriatal dopamine D2-receptor binding and social desirability
- 2010
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Ingår i: NeuroImage. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1053-8119 .- 1095-9572. ; 50:1, s. 323-328
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Tidskriftsartikel (refereegranskat)abstract
- Research on the biological underpinnings of personality can provide leads to the pathophysiology of psychiatric disorders. In particular, interpersonal aspects of behavior are a common problem during the course of psychiatric illness. Animal research has demonstrated a role for the dopamine system in social behaviour, and recent molecular imaging studies have shown a negative correlation between dopamine D2-receptor binding in the striatum and social desirability. The emotional and cognitive aspects of social behavior suggest involvement of brain regions outside of the striatum, such as limbic structures. The aim of the present study was to explore associations between the personality trait social desirability and dopamine D2-receptor binding in both striatal and extrastriatal brain regions. We examined 16 control subjects with Positron Emission Tomography and the radioligands [C-11]raclopride and [C-11]FLB 457, in relation to social desirability in the inventory Swedish universities Scales of Personality. [C-11]raclopride D2-receptor binding in the striatum showed negative correlations to social desirability scores, corroborating previous findings. Furthermore, a correlation of a higher statistical significance was demonstrated for [C-11]FLB 457 binding in the hippocampal-amygdala complex. A separate analysis of social desirability items in relation to a model of interpersonal behaviour revealed that the associations were driven by items reflecting high submissiveness and high affiliation. Taken together with previous evidence on D2-receptor binding and social behaviour, a role for dopaminergic neurotransmission in regulating displays of dominance vs. submissive behaviour is proposed. (C) 2009 Elsevier B.V. All rights reserved.
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24. |
- Cervenka, Simon, et al.
(författare)
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Molecular imaging in schizophrenia
- 2020
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Ingår i: Neuroimaging in schizophrenia. - Cham : Springer Nature. - 9783030352066 ; , s. 145-159
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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25. |
- Cervenka, Simon, et al.
(författare)
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PET Studies of D2-Receptor Binding in Striatal and Extrastriatal Brain Regions : Biochemical Support In Vivo for Separate Dopaminergic Systems in Humans
- 2010
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Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 64:6, s. 478-485
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Tidskriftsartikel (refereegranskat)abstract
- Most molecular imaging studies of the dopamine (DA) system performed to date have focused on the striatum, a region receiving dense dopaminergic innervation. In clinical research on the DA D2-receptor, striatal binding has often been regarded as an index of global DA function, based on the underlying assumption of common regulatory mechanisms for receptor expression across brain regions. Recent data has challenged this view, suggesting differences in genetic regulation between striatal and extrastriatal brain regions. The relationship between binding levels in brain regions has, however, not been directly examined in the same sample. In this study, we searched for interregional correlations between DA D2-receptor availability as determined with Positron Emission Tomography in 16 control subjects. The radioligands [C-11]raclopride and [C-11]FLB 457 were used for measurements of D2-receptor binding in striatal and extrastriatal regions, respectively. No correlation was observed between D2-receptor availability in striatum and any of the extrastriatal regions, as assessed using both region of interest- and voxel-based analyses. Instead, the pattern of correlations was consistent with the model of separate dopaminergic systems as has been originally observed in rodents. These preliminary results encourage approaches searching for individual patterns of receptor binding across the whole brain volume in clinical studies on the dopamine system.
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26. |
- 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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27. |
- 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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28. |
- 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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29. |
- de Manzano, Orjan, et al.
(författare)
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Individual differences in the proneness to have flow experiences are linked to dopamine D2-receptor availability in the dorsal striatum
- 2013
-
Ingår i: NeuroImage. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1053-8119 .- 1095-9572. ; 67, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Flow is a subjective experience of high but effortless attention, enjoyment, and low self-awareness that can occur during the active performance of challenging tasks. The dispositional proneness to experience flow is associated with personality traits that are known to be influenced by dopaminergic neural systems. Here, for the first time, we investigated relations between flow proneness and dopaminergic function. Specifically, we tested the hypothesis that the availability of dopamine D2-receptors in the striatum is positively associated with flow proneness. Striatal D2-receptor availability was measured in a sample of 25 healthy adults using positron emission tomography and [C-11]raclopride. Flow proneness was measured using the Swedish Flow Proneness Questionnaire. As hypothesized, there was a significant correlation (r = .41) between striatal D2-receptor availability and flow proneness. An exploratory analysis of striatal subregions showed that the relation was mainly driven by the dorsal striatum, with a significantly higher correlation in the putamen than in the ventral striatum. The findings constitute the first demonstration of an association between flow proneness and dopaminergic function. We suggest that the proneness to experience flow is related to personality dimensions that are under dopaminergic control and characterized by low impulsiveness, stable emotion, and positive affect. (C) 2012 Elsevier Inc. All rights reserved.
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30. |
- de Manzano, Örjan, et al.
(författare)
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Thinking Outside a Less Intact Box : Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals
- 2010
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence support that dopaminergic neurotransmission plays a role in creative thought and behavior. Here, we investigated the relationship between creative ability and dopamine D2 receptor expression in healthy individuals, with a focus on regions where aberrations in dopaminergic function have previously been associated with psychotic symptoms and a genetic liability to schizophrenia. Scores on divergent thinking tests (Inventiveness battery, Berliner Intelligenz Struktur Test) were correlated with regional D2 receptor densities, as measured by Positron Emission Tomography, and the radioligands [C-11] raclopride and [C-11]FLB 457. The results show a negative correlation between divergent thinking scores and D2 density in the thalamus, also when controlling for age and general cognitive ability. Hence, the results demonstrate that the D2 receptor system, and specifically thalamic function, is important for creative performance, and may be one crucial link between creativity and psychopathology. We suggest that decreased D2 receptor densities in the thalamus lower thalamic gating thresholds, thus increasing thalamocortical information flow. In healthy individuals, who do not suffer from the detrimental effects of psychiatric disease, this may increase performance on divergent thinking tests. In combination with the cognitive functions of higher order cortical networks, this could constitute a basis for the generative and selective processes that underlie real life creativity.
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31. |
- Elvsashagen, T, et al.
(författare)
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The genetic architecture of human brainstem structures and their involvement in common brain disorders
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4016-
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Tidskriftsartikel (refereegranskat)abstract
- Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.
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32. |
- Farde, Lars, et al.
(författare)
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Brain neuroreceptor density and personality traits : towards dimensional biomarkers for psychiatric disorders.
- 2018
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Ingår i: Philosophical Transactions of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8436 .- 1471-2970. ; 373:1744
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Forskningsöversikt (refereegranskat)abstract
- Positron emission tomography has, for 30 years, been used in numerous case-control studies searching for hypothesized differences in the density of neuroreceptor or transporter proteins in psychiatric disorders such as schizophrenia and depression. In most cases, the results have not been conclusive. One reason could be the sizeable interindividual variability in biochemical markers, which in twin studies have shown to emanate from both environmental and genetic factors, leading to low statistical power for the detection of group effects. On the other hand, the same interindividual variability has served as an opportunity for correlative studies on the biological underpinning of behaviour. Using this approach, a series of studies has linked markers for the dopamine and serotonin system to personality traits associated with psychiatric conditions. Based on increasing evidence for the view that many psychopathological states represent extremes of a continuum rather than distinct categories, this research strategy may lead to new biological insights about the vulnerability to and pathophysiology of major psychiatric disorders.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.
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33. |
- Fatouros-Bergman, Helena, et al.
(författare)
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Meta-analysis of cognitive performance in drug-naive patients with schizophrenia
- 2014
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Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964 .- 1573-2509. ; 158:1-3, s. 156-162
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive deficits represent a significant characteristic of schizophrenia. However, a majority of the clinical studies have been conducted in antipsychotic drug treated patients. Thus, it remains unclear if significant cognitive impairments exist in the absence of medication. This is the first meta-analysis of cognitive findings in drug-na ve patients with schizophrenia. Cognitive data from 23 studies encompassing 1106 patients and 1385 controls published from 1992 to 2013 were included. Tests were to a large extent ordered in cognitive domains according to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. Analysis was performed with STATA using the random-effects model and heterogeneity as well as Egger's publication bias was assessed. Overall the results show that patients performed worse than healthy controls in all cognitive domains with medium to large effect sizes. Verbal memory, speed of processing and working memory were three of the domains with the greatest impairments. The pattern of results is in line with previous meta-analytic findings in antipsychotic treated patients. The present meta-analysis confirms the existence of significant cognitive impairments at the early stage of the illness in the absence of antipsychotic medication.
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34. |
- 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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35. |
- Freiburghaus, Tove, et al.
(författare)
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Low convergent validity of [11C]raclopride binding in extrastriatal brain regions : A PET study of within-subject correlations with [11C]FLB 457
- 2021
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 226
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Tidskriftsartikel (refereegranskat)abstract
- Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test-retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [11C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centers. Instead, the medium affinity radioligand [11C]raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [11C]raclopride in extrastriatal regions in a pharmacological competition study with quetiapine. Here, we utilise a data set of 16 healthy control subjects examined with both [11C]raclopride and [11C]FLB 457 to assess the correlation in binding potential (BPND) in extrastriatal brain regions. BPND was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BPND values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [11C]raclopride and [11C]FLB 457 BPND extrastriatally (Pearson's R: 0.30-0.56), in contrast to very strong correlations between repeated [11C]FLB 457 measurements (Pearson's R: 0.82-0.98). In comparison, correlations between repeated [11C]raclopride measurements were low to moderate (Pearson's R: 0.28-0.75). These results are likely related to low signal to noise ratio of [11C]raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [11C]raclopride should be interpreted with caution.
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36. |
- Fridén, Markus, et al.
(författare)
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Identification of positron emission tomography (PET) tracer candidates by prediction of the target-bound fraction in the brain
- 2014
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 4, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Development of tracers for imaging with positron emission tomography (PET) is often a time-consuming process associated with considerable attrition. In an effort to simplify this process, we herein propose a mechanistically integrated approach for the selection of tracer candidates based on in vitro measurements of ligand affinity (K-d), non-specific binding in brain tissue (V-u,V-brain), and target protein expression (B-max). Methods: A dataset of 35 functional and 12 non-functional central nervous system (CNS) PET tracers was compiled. Data was identified in literature for K-d and B-max, whereas a brain slice methodology was used to determine values for V-u,V-brain. A mathematical prediction model for the target-bound fraction of tracer in the brain (f(tb)) was derived and evaluated with respect to how well it predicts tracer functionality compared to traditional PET tracer candidate selection criteria. Results: The methodology correctly classified 31/35 functioning and 12/12 non-functioning tracers. This predictivity was superior to traditional classification criteria or combinations thereof. Conclusions: The presented CNS PET tracer identification approach is rapid and accurate and is expected to facilitate the development of novel PET tracers for the molecular imaging community.
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37. |
- Goodwin, Richard J A, et al.
(författare)
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Qualitative and Quantitative MALDI Imaging of the Positron Emission Tomography Ligands Raclopride (a D2 Dopamine Antagonist) and SCH 23390 (a D1 Dopamine Antagonist) in Rat Brain Tissue Sections Using a Solvent-Free Dry Matrix Application Method
- 2011
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 83:24, s. 9694-9701
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Tidskriftsartikel (refereegranskat)abstract
- The distributions of positron emission tomography (PET) ligands in rat brain tissue sections were analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). The detection of the PET ligands was possible following the use of a solvent-free dry MALDI matrix application method employing finely ground dry α-cyano-4-hydroxycinnamic acid (CHCA). The D2 dopamine receptor antagonist 3,5-dichloro-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-hydroxy-6-methoxybenzamide (raclopride) and the D1 dopamine receptor antagonist 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol (SCH 23390) were both detected at decreasing abundance at increasing period postdosing. Confirmation of the compound identifications and distributions was achieved by a combination of mass-to-charge ratio accurate mass, isotope distribution, and MS/MS fragmentation imaging directly from tissue sections (performed using MALDI TOF/TOF, MALDI q-TOF, and 12T MALDI-FT-ICR mass spectrometers). Quantitative data was obtained by comparing signal abundances from tissues to those obtained from quantitation control spots of the target compound applied to adjacent vehicle control tissue sections (analyzed during the same experiment). Following a single intravenous dose of raclopride (7.5 mg/kg), an average tissue concentration of approximately 60 nM was detected compared to 15 nM when the drug was dosed at 2 mg/kg, indicating a linear response between dose and detected abundance. SCH 23390 was established to have an average tissue concentration of approximately 15 μM following a single intravenous dose at 5 mg/kg. Both target compounds were also detected in kidney tissue sections when employing the same MSI methodology. This study illustrates that a MSI may well be readily applied to PET ligand research development when using a solvent-free dry matrix coating.
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38. |
- Griffioen, Gina, et al.
(författare)
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Serotonin 5-HT1A receptor binding and self-transcendence in healthy control subjects : a replication study using Bayesian hypothesis testing
- 2018
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Ingår i: PeerJ. - : PeerJ. - 2167-8359. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Objective. A putative relationship between markers for the serotonin system and the personality scale self-transcendence (ST) and its subscale spiritual acceptance (SA) has been demonstrated in a previous PET study of 5-HT1A receptor binding in healthy control subjects. The results could however not be replicated in a subsequent PET study at an independent centre. In this study, we performed a replication of our original study in a larger sample using Bayesian hypothesis testing to evaluate relative evidence both for and against this hypothesis. Methods. Regional 5-HT1A receptor binding potential (BPND) was examined in 50 healthy male subjects using PET with the radioligand [C-11]WAY100635. 5-HT1A availability was calculated using the simplified reference tissue model (SRTM) yielding regional BPND. ST and SA were measured using the Temperament and Character Inventory (TCI) questionnaire. Correlations between ST/SA scores and 5-HT1A BPND in frontal cortex, hippocampus and raphe nuclei were examined by calculation of default correlation Bayes factors (BFs) and replication BFs. Results. There were no significant correlations between 5-HT1A receptor binding and ST/SA scores. Rather, five of six replication BFs provided moderate to strong evidence for no association between 5-HT1A availability and ST/SA, while the remaining BF provided only weak evidence. Conclusion. We could not replicate our previous findings of an association between 5-HT1A availability and the personality trait ST/SA. Rather, the Bayesian analysis provided evidence for a lack of correlation. Further research should focus on whether other components of the serotonin system may be related to ST or SA. This study also illustrates how Bayesian hypothesis testing allows for greater flexibility and more informative conclusions than traditional p-values, suggesting that this approach may be advantageous for analysis of molecular imaging data.
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39. |
- Guterstam, Joar, et al.
(författare)
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Effects of amphetamine on the human brain opioid system : a positron emission tomography study
- 2013
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Ingår i: International Journal of Neuropsychopharmacology. - : Oxford University Press (OUP). - 1461-1457 .- 1469-5111. ; 16:4, s. 763-769
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Tidskriftsartikel (refereegranskat)abstract
- Studies in rodents have shown that psychostimulant drugs such as cocaine and amphetamine cause endorphin release in the brain reward system. There is also evidence for the involvement of the opioid system in human psychostimulant dependence. The acute effects of an i.v. psychostimulant drug on the brain opioid system, however, have not yet been investigated in humans. We hypothesized that an i.v. dose of amphetamine as compared to placebo would cause an opioid release in the human brain reward system, measurable as a reduction of the binding potential of the m-opioid receptor radioligand [C-11] carfentanil. Ten healthy young men were examined using positron emission tomography (PET) and [C-11] carfentanil in three sessions : at baseline; after placebo; after an i.v. amphetamine dose of 0.3 mg/kg bodyweight. The order of amphetamine and placebo was double-blinded and randomized. PET examinations were performed with a Siemens high resolution research tomograph. Data were analysed with the simplified reference tissue model, applying manually drawn regions of interest for every subject. Using repeated measures analysis of variance, we found no significant differences in [C-11] carfentanil binding potential between amphetamine and placebo conditions in any of the investigated brain regions. In contrast to data from rodent studies and a recent study of oral amphetamine administration in humans, an i.v. dose of amphetamine does not cause any acute opioid release in healthy human subjects. The postulated role of the opioid system in mediating the effects of amphetamine needs to be further investigated in animal models of the disease as well as in patient populations.
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40. |
- Henningsson, Susanne, 1977, et al.
(författare)
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Genetic Variation in Brain-Derived Neurotrophic Factor Is Associated with Serotonin Transporter but Not Serotonin-1A Receptor Availability in Men
- 2009
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 66:5, s. 477-485
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Tidskriftsartikel (refereegranskat)abstract
- Background: The serotonergic system, including the serotonin transporter (5-HTT), which is the target of many antidepressants, seems to be influenced by brain-derived neurotrophic factor (BDNF). Methods: Positron emission tomography (PET) was used to address, in 25 and 53 healthy volunteers, respectively, the possible association between six polymorphisms in the gene encoding BDNF and the availability of two proteins expressed by serotonergic neurons: the 5-HTT, measured with the radioligand [C-11]MADAM, and the serotonin-1A (5-HT1A) receptor, measured with [C-11]WAY-100635. Results: Several single nucleotide polymorphisms were associated with [C-11]MADAM binding potential (BP) in most brain regions, male carriers of the valine/valine genotype of the Val66Met polymorphism displaying higher availability. Effect sizes ranged from a 50% to a threefold increase. In contrast, there was no association for [C-11]WAY-100635 BP. The observation that BDNF polymorphisms were associated with 5-HTT availability could be partly replicated in an independent population comprising nine male suicide attempters and nine matched control subjects, in which transporter availability had been measured with single photon emission computed tomography with I-123-beta-CIT as ligand. Conclusions: Our results suggest that genetic variation in BDNF influences 5-HTT but not 5-HT1A receptor density in the human brain.
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41. |
- Jangard, Simon, et al.
(författare)
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Striatal dopamine D2 receptor availability as a predictor of subsequent alcohol use in social drinkers.
- 2023
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Ingår i: Addiction. - : Wiley. - 0965-2140 .- 1360-0443. ; 118:6, s. 1053-1061
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8-to-16-years post PET scan, in social drinkers.DESIGN: Longitudinal study following healthy individuals.SETTING: Academic research imaging centre in Stockholm, Sweden.PARTICIPANTS: 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies.MEASUREMENTS: One PET examination with the D2R antagonist radioligand [11 C]raclopride at baseline, and self-report measures assessing alcohol use, drug use, impulsivity, reward sensitivity, and family history of alcohol- or substance use disorder at follow-up.FINDINGS: We found no evidence for an association between D2R availability and later alcohol use (B = -.019, B 95% confidence interval [CI] = -.043-(-).006, p = .147), nor for the majority of the alcohol-related factors (B 95 % CI = -.034-.004, p = .273-.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -.017, B 95% CI = -.034-(-).001, p = .046).CONCLUSIONS: Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder.
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42. |
- Kanegawa, Naoki, et al.
(författare)
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In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects
- 2016
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 54, s. 149-157
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Tidskriftsartikel (refereegranskat)abstract
- Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [C-11]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [C-11]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. (C) 2016 Elsevier Inc. All rights reserved.
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43. |
- Karabanov, Anke, et al.
(författare)
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Dopamine D2 receptor density in the limbic striatum is related to implicit but not explicit movement sequence learning
- 2010
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 107:16, s. 7574-7579
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Tidskriftsartikel (refereegranskat)abstract
- A large body of literature suggests that motor sequence learning involves dopamine-modulated plastic processes in the basal ganglia. Sequence learning can occur both implicitly, without conscious awareness and intention to learn, and explicitly, i.e., under conscious control. Here, we investigated whether individual differences in implicit and explicit sequence learning of movement sequences in a group of 15 healthy participants are related to dopamine D2 receptor densities in functional subregions of the striatum. Sequence learning was assessed using the serial reaction time task, and measures of implicit and explicit knowledge were estimated using a process dissociation procedure. Correlation analyses were performed between these measures and D2 receptor densities, which had been measured previously with positron emission tomography. Striatal D2 densities were negatively related to measures of sequence learning. In the limbic subregion, D2 densities were specifically related to implicit but not explicit learning. These findings suggest that individual differences in striatal DA function underlie differences in sequence learning ability and support that implicit and explicit sequence learning depend on partly distinct neural circuitry. The findings are also in line with the general view that implicit learning systems are evolutionarily primitive and tend to rely more on phylogenetically old neural circuitry than does explicit learning and cognition.
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44. |
- Larsson, Maria, et al.
(författare)
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Age-related loss of olfactory sensitivity : Association to dopamine transporter binding in putamen
- 2009
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Ingår i: Neuroscience. - : Elsevier Ltd.. - 0306-4522 .- 1873-7544. ; 161:2, s. 422-426
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Tidskriftsartikel (refereegranskat)abstract
- The relationship between age-related reductions in the binding potential for the striatal dopamine transporter (DAT) and age-related deficits in olfactory sensitivity was examined in 12 subjects ranging from 36 to 82 years of age. Positron emission tomography (PET) and the radioligand [11C]β-CIT-FE were used to determine DAT binding in two striatal regions, the caudate and the putamen. The results showed age-related losses of DAT binding from early to late adulthood of similar size for caudate and putamen, and there was a pronounced age deterioration in olfactory sensitivity. Importantly, the age-related olfactory deficit was associated with reductions in DAT binding in putamen, but not caudate. Also, DAT binding in putamen added systematic variance in odor threshold after controlling for age. The findings indicate that DAT binding in putamen is related to age-related olfactory deficits, as well as to odor sensitivity independently of age.
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45. |
- Lee, Maria, et al.
(författare)
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No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis
- 2021
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Ingår i: NPJ SCHIZOPHRENIA. - : Springer Nature. - 2334-265X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [C-11]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (beta = 0.013-0.074, partial r= -0.037-0.273, p = 0.131-0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BFH0:H1 = 3.3-8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations.
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46. |
- Maguire Jr., Gerald Q., et al.
(författare)
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Evaluation of Errors Using Graphical Techniques
- 1987
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Ingår i: Proceedings of the Twentieth Annual Hawaii International Conference on System Sciences. - : IEEE and ACM. ; , s. 9-15
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Konferensbidrag (refereegranskat)abstract
- Anatomic localization in functional (such as PET) imaging, often requires a structural (such as CT or NMRI) study of the brain in the same plane. Some neuropsychiatric conditions make it difficult for a patient to hold his/her head immobile even when a rigid head holder is used. We studied the effect of tilt of the anatomic reference image, in this instance CT, relative to the functional image, here PET, on the quantification of receptor ligand concentration in anatomically defined regions of the brain.
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47. |
- Maguire Jr., Gerald Q., et al.
(författare)
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Use of graphical techniques for error evaluation
- 1987
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Ingår i: Journal of medical systems. - : Springer. - 0148-5598 .- 1573-689X. ; 11:4, s. 277-286
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Tidskriftsartikel (refereegranskat)abstract
- Anatomic localization in functional (such as PET) imaging often requires a structural (such as CT or NMRI) study of the brain in the same plane. Some neuropsychiatric conditions make it difficult for a patient to hold his/her head immobile even when a rigid head holder is used. We studied the effect of tilt of the anatomic reference image, in this instance CT, relative to the functional image, here PET, on the quantification of receptor ligand concentration in anatomically defined regions of the brain.
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48. |
- 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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49. |
- 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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50. |
- Matheson, Granville J, et al.
(författare)
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Dopamine D1 receptor availability is not associated with delusional ideation measures of psychosis proneness
- 2020
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Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964 .- 1573-2509. ; 222, s. 175-184
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Tidskriftsartikel (refereegranskat)abstract
- The dopamine D1 receptor (D1R) is thought to play a role in psychosis and schizophrenia, however positron emission tomography studies comparing patients and controls have been inconsistent. To circumvent some of the limitations of clinical studies, such as antipsychotic exposure, an alternative approach is to examine subclinical psychotic symptoms within the general population, i.e. psychosis proneness traits. In this study, we investigated whether D1R availability is associated with delusional ideation in healthy controls, in four experiments, using [11C]SCH23390 PET (n = 76) and psychometric questionnaires (n = 217). We performed exploratory analyses, direct self-replication, and confirmatory analyses using Bayesian statistical modelling. Collectively, we found strong evidence that there is little to no linear association between delusional ideation and D1R. If hypothesised changes in D1R in drug-naive psychosis patients can be confirmed, our results suggest that they may either occur at disease onset, or that they are associated with specific aspects of psychosis other than delusional ideation.
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