| 1. |
- Braniste, Viorica, et al.
(författare)
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The gut microbiota influences blood-brain barrier permeability in mice
- 2014
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 6:263, s. 263ra158-
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Tidskriftsartikel (refereegranskat)abstract
- Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- Eriksson, Olof, et al.
(författare)
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In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass
- 2010
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 37:3, s. 357-363
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The positron emission tomography (PET) tracer 9-[(18)F]fluoroethyl-(+)-dihydrotetrabenazine ([(18)F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass. METHODS: Three pigs were intravenously administered [(18)F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k(D) and B(max) were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls. RESULTS: [(18)F]-FE-(+)-DTBZ had a k(D) of 3.5+/-1.0 nM, a B(max) of 382+/-108 fmol/mg protein and a specificity of 89+/-1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone. CONCLUSIONS: [(18)F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [(18)F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.
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| 6. |
- 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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| 7. |
- Guerrero, José-Luis, 1977-, et al.
(författare)
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Exploring the hydrological robustness of model-parameter values with alpha shapes
- 2013
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Ingår i: Water resources research. - : American Geophysical Union (AGU). - 0043-1397 .- 1944-7973. ; 49:10, s. 6700-6715
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Tidskriftsartikel (refereegranskat)abstract
- Estimation of parameter values in hydrological models has gradually moved from subjective, trial-and-error methods into objective estimation methods. Translation of nature's complexity to bit operations is an uncertain process as a result of data errors, epistemic gaps, computational deficiencies, and other limitations, and relies on calibration to fit model output to observed data. The robustness of the calibrated parameter values to these types of uncertainties is therefore an important concern. In this study, we investigated how the hydrological robustness of the model-parameter values varied within the geometric structure of the behavioral (well-performing) parameter space with a depth function based on α shapes and an in-depth posterior performance analysis of the simulations in relation to the observed discharge uncertainty. The α shape depth is a nonconvex measure that may provide an accurate and tight delimitation of the geometric structure of the behavioral space for both unimodal and multimodal parameter-value distributions. WASMOD, a parsimonious rainfall-runoff model, was applied to six Honduran and one UK catchment, with differing data quality and hydrological characteristics. Model evaluation was done with two performance measures, the Nash-Sutcliffe efficiency and one based on flow-duration curves. Deep parameter vectors were in general found to be more hydrologically robust than shallow ones in the analyses we performed; model-performance values increased with depth, deviations to the observed data for the high-flow aspects of the hydrograph generally decreased with increasing depth, deep parameter vectors generally transferred in time with maintained high performance values, and the model had a low sensitivity to small changes in the parameter values. The tight delimitation of the behavioral space provided by the α shapes depth function showed a potential to improve the efficiency of calibration techniques that require further exploration. For computational reasons only a three-parameter model could be used, which limited the applicability of this depth measure and the conclusions drawn in this paper, especially concerning hydrological robustness at low flows.
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| 8. |
- Guerrero, Jose-Luis, et al.
(författare)
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Temporal variability in stage-discharge relationships
- 2012
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Ingår i: Journal of Hydrology. - : Elsevier BV. - 0022-1694 .- 1879-2707. ; 446, s. 90-102
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Tidskriftsartikel (refereegranskat)abstract
- Although discharge estimations are central for water management and hydropower, there are few studies on the variability and uncertainty of their basis; deriving discharge from stage heights through the use of a rating curve that depends on riverbed geometry. A large fraction of the world's river-discharge stations are presumably located in alluvial channels where riverbed characteristics may change over time because of erosion and sedimentation. This study was conducted to analyse and quantify the dynamic relationship between stage and discharge and to determine to what degree currently used methods are able to account for such variability. The study was carried out for six hydrometric stations in the upper Choluteca River basin, Honduras, where a set of unusually frequent stage-discharge data are available. The temporal variability and the uncertainty of the rating curve and its parameters were analysed through a Monte Carlo (MC) analysis on a moving window of data using the Generalised Likelihood Uncertainty Estimation (GLUE) methodology. Acceptable ranges for the values of the rating-curve parameters were determined from riverbed surveys at the six stations, and the sampling space was constrained according to those ranges, using three-dimensional alpha shapes. Temporal variability was analysed in three ways: (i) with annually updated rating curves (simulating Honduran practices), (ii) a rating curve for each time window, and (iii) a smoothed, continuous dynamic rating curve derived from the MC analysis. The temporal variability of the rating parameters translated into a high rating-curve variability. The variability could turn out as increasing or decreasing trends and/or cyclic behaviour. There was a tendency at all stations to a seasonal variability. The discharge at a given stage could vary by a factor of two or more. The quotient in discharge volumes estimated from dynamic and static rating curves varied between 0.5 and 1.5. The difference between discharge volumes derived from static and dynamic curves was largest for sub-daily ratings but stayed large also for monthly and yearly totals. The relative uncertainty was largest for low flows but it was considerable also for intermediate and large flows. The standard procedure of adjusting rating curves when calculated and observed discharge differ by more than 5% would have required continuously updated rating curves at the studied locations. We believe that these findings can be applicable to many other discharge stations around the globe.
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| 9. |
- 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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| 10. |
- Jahan, Mahabuba, et al.
(författare)
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Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET
- 2011
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Ingår i: EJNMMI Research. - 2191-219X. ; 1:1, s. 33-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundFluorine-18 dihydrotetrabenazine [DTBZ] analogues, which selectively target the vesicular monoamine transporter 2 [VMAT2], have been extensively studied for in vivo quantification of beta cell mass by positron-emission tomography [PET]. This study describes a novel deuterated radioligand [18F]fluoroethyl [FE]-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [18F]FE-DTBZ.Methods[18F]FE-DTBZ-d4 was synthesized by alkylation of 9-O-desmethyl-(+)-DTBZ precursor with deuterated [18F]FE bromide ([18F]FCD2CD2Br). Radioligand binding potential [BP] was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo pharmacokinetics and pharmacodynamics [PK/PD] was studied in a porcine model by PET/computed tomography, and the rate of defluorination was quantified by compartmental modeling.Results[18F]FE-DTBZ-d4 was produced in reproducible good radiochemical yield in 100 ± 20 min. Radiochemical purity of the formulated product was > 98% for up to 5 h with specific radioactivities that ranged from 192 to 529 GBq/μmol at the end of the synthesis. The in vitro BP for VMAT2 in the islet tissue was 27.0 ± 8.8, and for the exocrine tissue, 1.7 ± 1.0. The rate of in vivo defluorination was decreased significantly (kdefluorination = 0.0016 ± 0.0007 min-1) compared to the non-deuterated analogue (kdefluorination = 0.012 ± 0.002 min-1), resulting in a six fold increase in half-life stability.Conclusions[18F]FE-DTBZ-d4 has similar PK and PD properties for VMAT2 imaging as its non-deuterated analogue [18F]FE-DTBZ in addition to gaining significantly increased stability against defluorination. [18F]FE-DTBZ-d4 is a prime candidate for future preclinical and clinical studies on focal clusters of beta cells, such as in intramuscular islet grafts.
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