Publications by authors named "Simon Cervenka"

70 Publications

Plasma bilirubin levels are reduced in first-episode psychosis patients and associates to working memory and duration of untreated psychosis.

Sci Rep 2021 Apr 6;11(1):7527. Epub 2021 Apr 6.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.

Schizophrenia is a severe mental disorder and one of its characteristics is cognitive impairments. Findings regarding levels of the heme metabolite and plasma antioxidant bilirubin in schizophrenia are inconclusive. However, a recently published study indicate that low levels of bilirubin may be implicated in the memory impairments seen in the disorder. The aim of this cross-sectional study was to investigate the levels of bilirubin in individuals with a first-episode psychosis (FEP) and to examine if bilirubin levels were associated to cognitive impairments, symptoms and duration of untreated psychosis (DUP). Bilirubin levels were reduced in 39 individuals with FEP compared with 20 HC (median [IQR]: 11.0 [9.0-13.0] µM vs. 15.0 [11.5-18.5] µM). In individuals with FEP, bilirubin levels were also positively correlated to two working memory tests (r = 0.40 and r = 0.32) and inversely correlated to DUP (r = - 0.36). Findings were not influenced by confounding factors. The results confirm the antioxidant deficit previously seen in schizophrenia, but also indicate that these changes may be related to DUP. The study also confirms that bilirubin may be implicated in the cognitive deficits that accompanies the disorder, here for the first time presented in individuals with FEP.
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http://dx.doi.org/10.1038/s41598-021-87096-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024299PMC
April 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Authors:
Sophia Frangou Amirhossein Modabbernia Steven C R Williams Efstathios Papachristou Gaelle E Doucet Ingrid Agartz Moji Aghajani Theophilus N Akudjedu Anton Albajes-Eizagirre Dag Alnaes Kathryn I Alpert Micael Andersson Nancy C Andreasen Ole A Andreassen Philip Asherson Tobias Banaschewski Nuria Bargallo Sarah Baumeister Ramona Baur-Streubel Alessandro Bertolino Aurora Bonvino Dorret I Boomsma Stefan Borgwardt Josiane Bourque Daniel Brandeis Alan Breier Henry Brodaty Rachel M Brouwer Jan K Buitelaar Geraldo F Busatto Randy L Buckner Vincent Calhoun Erick J Canales-Rodríguez Dara M Cannon Xavier Caseras Francisco X Castellanos Simon Cervenka Tiffany M Chaim-Avancini Christopher R K Ching Victoria Chubar Vincent P Clark Patricia Conrod Annette Conzelmann Benedicto Crespo-Facorro Fabrice Crivello Eveline A Crone Anders M Dale Udo Dannlowski Christopher Davey Eco J C de Geus Lieuwe de Haan Greig I de Zubicaray Anouk den Braber Erin W Dickie Annabella Di Giorgio Nhat Trung Doan Erlend S Dørum Stefan Ehrlich Susanne Erk Thomas Espeseth Helena Fatouros-Bergman Simon E Fisher Jean-Paul Fouche Barbara Franke Thomas Frodl Paola Fuentes-Claramonte David C Glahn Ian H Gotlib Hans-Jörgen Grabe Oliver Grimm Nynke A Groenewold Dominik Grotegerd Oliver Gruber Patricia Gruner Rachel E Gur Ruben C Gur Tim Hahn Ben J Harrison Catharine A Hartman Sean N Hatton Andreas Heinz Dirk J Heslenfeld Derrek P Hibar Ian B Hickie Beng-Choon Ho Pieter J Hoekstra Sarah Hohmann Avram J Holmes Martine Hoogman Norbert Hosten Fleur M Howells Hilleke E Hulshoff Pol Chaim Huyser Neda Jahanshad Anthony James Terry L Jernigan Jiyang Jiang Erik G Jönsson John A Joska Rene Kahn Andrew Kalnin Ryota Kanai Marieke Klein Tatyana P Klyushnik Laura Koenders Sanne Koops Bernd Krämer Jonna Kuntsi Jim Lagopoulos Luisa Lázaro Irina Lebedeva Won Hee Lee Klaus-Peter Lesch Christine Lochner Marise W J Machielsen Sophie Maingault Nicholas G Martin Ignacio Martínez-Zalacaín David Mataix-Cols Bernard Mazoyer Colm McDonald Brenna C McDonald Andrew M McIntosh Katie L McMahon Genevieve McPhilemy Susanne Meinert José M Menchón Sarah E Medland Andreas Meyer-Lindenberg Jilly Naaijen Pablo Najt Tomohiro Nakao Jan E Nordvik Lars Nyberg Jaap Oosterlaan Víctor Ortiz-García de la Foz Yannis Paloyelis Paul Pauli Giulio Pergola Edith Pomarol-Clotet Maria J Portella Steven G Potkin Joaquim Radua Andreas Reif Daniel A Rinker Joshua L Roffman Pedro G P Rosa Matthew D Sacchet Perminder S Sachdev Raymond Salvador Pascual Sánchez-Juan Salvador Sarró Theodore D Satterthwaite Andrew J Saykin Mauricio H Serpa Lianne Schmaal Knut Schnell Gunter Schumann Kang Sim Jordan W Smoller Iris Sommer Carles Soriano-Mas Dan J Stein Lachlan T Strike Suzanne C Swagerman Christian K Tamnes Henk S Temmingh Sophia I Thomopoulos Alexander S Tomyshev Diana Tordesillas-Gutiérrez Julian N Trollor Jessica A Turner Anne Uhlmann Odile A van den Heuvel Dennis van den Meer Nic J A van der Wee Neeltje E M van Haren Dennis van 't Ent Theo G M van Erp Ilya M Veer Dick J Veltman Aristotle Voineskos Henry Völzke Henrik Walter Esther Walton Lei Wang Yang Wang Thomas H Wassink Bernd Weber Wei Wen John D West Lars T Westlye Heather Whalley Lara M Wierenga Katharina Wittfeld Daniel H Wolf Amanda Worker Margaret J Wright Kun Yang Yulyia Yoncheva Marcus V Zanetti Georg C Ziegler Paul M Thompson Danai Dima

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Authors:
Danai Dima Amirhossein Modabbernia Efstathios Papachristou Gaelle E Doucet Ingrid Agartz Moji Aghajani Theophilus N Akudjedu Anton Albajes-Eizagirre Dag Alnaes Kathryn I Alpert Micael Andersson Nancy C Andreasen Ole A Andreassen Philip Asherson Tobias Banaschewski Nuria Bargallo Sarah Baumeister Ramona Baur-Streubel Alessandro Bertolino Aurora Bonvino Dorret I Boomsma Stefan Borgwardt Josiane Bourque Daniel Brandeis Alan Breier Henry Brodaty Rachel M Brouwer Jan K Buitelaar Geraldo F Busatto Randy L Buckner Vincent Calhoun Erick J Canales-Rodríguez Dara M Cannon Xavier Caseras Francisco X Castellanos Simon Cervenka Tiffany M Chaim-Avancini Christopher R K Ching Victoria Chubar Vincent P Clark Patricia Conrod Annette Conzelmann Benedicto Crespo-Facorro Fabrice Crivello Eveline A Crone Udo Dannlowski Anders M Dale Christopher Davey Eco J C de Geus Lieuwe de Haan Greig I de Zubicaray Anouk den Braber Erin W Dickie Annabella Di Giorgio Nhat Trung Doan Erlend S Dørum Stefan Ehrlich Susanne Erk Thomas Espeseth Helena Fatouros-Bergman Simon E Fisher Jean-Paul Fouche Barbara Franke Thomas Frodl Paola Fuentes-Claramonte David C Glahn Ian H Gotlib Hans-Jörgen Grabe Oliver Grimm Nynke A Groenewold Dominik Grotegerd Oliver Gruber Patricia Gruner Rachel E Gur Ruben C Gur Tim Hahn Ben J Harrison Catharine A Hartman Sean N Hatton Andreas Heinz Dirk J Heslenfeld Derrek P Hibar Ian B Hickie Beng-Choon Ho Pieter J Hoekstra Sarah Hohmann Avram J Holmes Martine Hoogman Norbert Hosten Fleur M Howells Hilleke E Hulshoff Pol Chaim Huyser Neda Jahanshad Anthony James Terry L Jernigan Jiyang Jiang Erik G Jönsson John A Joska Rene Kahn Andrew Kalnin Ryota Kanai Marieke Klein Tatyana P Klyushnik Laura Koenders Sanne Koops Bernd Krämer Jonna Kuntsi Jim Lagopoulos Luisa Lázaro Irina Lebedeva Won Hee Lee Klaus-Peter Lesch Christine Lochner Marise W J Machielsen Sophie Maingault Nicholas G Martin Ignacio Martínez-Zalacaín David Mataix-Cols Bernard Mazoyer Colm McDonald Brenna C McDonald Andrew M McIntosh Katie L McMahon Genevieve McPhilemy Susanne Meinert José M Menchón Sarah E Medland Andreas Meyer-Lindenberg Jilly Naaijen Pablo Najt Tomohiro Nakao Jan E Nordvik Lars Nyberg Jaap Oosterlaan Víctor Ortiz-García de la Foz Yannis Paloyelis Paul Pauli Giulio Pergola Edith Pomarol-Clotet Maria J Portella Steven G Potkin Joaquim Radua Andreas Reif Daniel A Rinker Joshua L Roffman Pedro G P Rosa Matthew D Sacchet Perminder S Sachdev Raymond Salvador Pascual Sánchez-Juan Salvador Sarró Theodore D Satterthwaite Andrew J Saykin Mauricio H Serpa Lianne Schmaal Knut Schnell Gunter Schumann Kang Sim Jordan W Smoller Iris Sommer Carles Soriano-Mas Dan J Stein Lachlan T Strike Suzanne C Swagerman Christian K Tamnes Henk S Temmingh Sophia I Thomopoulos Alexander S Tomyshev Diana Tordesillas-Gutiérrez Julian N Trollor Jessica A Turner Anne Uhlmann Odile A van den Heuvel Dennis van den Meer Nic J A van der Wee Neeltje E M van Haren Dennis Van't Ent Theo G M van Erp Ilya M Veer Dick J Veltman Aristotle Voineskos Henry Völzke Henrik Walter Esther Walton Lei Wang Yang Wang Thomas H Wassink Bernd Weber Wei Wen John D West Lars T Westlye Heather Whalley Lara M Wierenga Steven C R Williams Katharina Wittfeld Daniel H Wolf Amanda Worker Margaret J Wright Kun Yang Yulyia Yoncheva Marcus V Zanetti Georg C Ziegler Paul M Thompson Sophia Frangou

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

Effects of acute glial cell activation on memory performance - Implications for treatment of cognitive symptoms in neurological and psychiatric disorders.

Authors:
Simon Cervenka

Brain Behav Immun 2021 Mar 21;93:8-9. Epub 2021 Jan 21.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, SE-171 76 Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2021.01.009DOI Listing
March 2021

Antipsychotic use among persons with schizophrenia in Sweden and Finland, trends and differences.

Nord J Psychiatry 2020 Dec 17:1-8. Epub 2020 Dec 17.

Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland.

Objectives: To compare the differences in prevalence of antipsychotic and adjunctive pharmacotherapy use among individuals with schizophrenia between Sweden and Finland during 2006-2016.

Methods: Nationwide register-based data were utilized for constructing two separate cohorts: all persons in Finland with a diagnosis of schizophrenia treated in inpatient care during 1972-2014, and persons in Sweden aged 16-64 with recorded diagnoses of schizophrenia in inpatient or specialized outpatient care, sickness absence or disability pension during 2005-2013. The prevalence of use was assessed as a point prevalence on 31 October each year 2006-2016, based on drug use periods modelled with the PRE2DUP method. In 2016, the Finnish cohort included 37,780 persons and Swedish cohort 25,433 persons.

Results: The most commonly used antipsychotic in 2016 was oral olanzapine in both countries (22.7% [95% CI 21.6-22.4] in Finland, 20.9% [20.4-21.4] in Sweden), followed by clozapine which was more frequently used in Finland (22.0%, 21.6-22.4) than in Sweden (14.8%, 14.4-15.3). Long-acting injectable (LAI) use was almost two times more likely in Sweden (21.6%, 95% CI 21.1-22.1) than in Finland (12.8%, 12.5-13.1), a difference which was due to more common use of FG-LAIs in Sweden. A four-fold difference was observed in Z-drugs use (19.9% in Sweden versus 5.0% in Finland).

Conclusion: Potential explanations for the observed discrepancies include differences in national treatment guidelines, methods of data collection, patient characteristics and/or attitudes towards treatment among both patients and physicians.
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http://dx.doi.org/10.1080/08039488.2020.1854853DOI Listing
December 2020

Low convergent validity of [C]raclopride binding in extrastriatal brain regions: A PET study of within-subject correlations with [C]FLB 457.

Neuroimage 2021 02 2;226:117523. Epub 2020 Nov 2.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm SE -171 76, Sweden.

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 [C]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 [C]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 [C]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 [C]raclopride and [C]FLB 457 to assess the correlation in binding potential (BP) in extrastriatal brain regions. BP was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BP 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 [C]raclopride and [C]FLB 457 BP extrastriatally (Pearson's R: 0.30-0.56), in contrast to very strong correlations between repeated [C]FLB 457 measurements (Pearson's R: 0.82-0.98). In comparison, correlations between repeated [C]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 [C]raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [C]raclopride should be interpreted with caution.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117523DOI Listing
February 2021

Neuroinflammation in psychiatric disorders: PET imaging and promising new targets.

Lancet Psychiatry 2020 12 21;7(12):1064-1074. Epub 2020 Oct 21.

Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA. Electronic address:

Neuroinflammation is a multifaceted physiological and pathophysiological response of the brain to injury and disease. Given imaging findings of 18 kDa translocator protein (TSPO) and the development of radioligands for other inflammatory targets, PET imaging of neuroinflammation is at a particularly promising stage. This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis disorders, substance use, and obsessive-compulsive disorder. We also consider promising new targets that can be measured in the brain, such as monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, colony stimulating factor 1 receptor, and the purinergic P2X7 receptor. Thus far, the most compelling TSPO imaging results have arguably been found in major depressive disorder, for which consistent increases have been observed, and in schizophrenia and psychosis, for which patients show reduced TSPO levels. This pattern highlights the importance of validating brain biomarkers of neuroinflammation for each condition separately before moving on to patient stratification and treatment monitoring trials.
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http://dx.doi.org/10.1016/S2215-0366(20)30255-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893630PMC
December 2020

Brain Age Prediction Reveals Aberrant Brain White Matter in Schizophrenia and Bipolar Disorder: A Multisample Diffusion Tensor Imaging Study.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 12 8;5(12):1095-1103. Epub 2020 Jul 8.

Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway; KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address:

Background: Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts.

Methods: We trained 6 cross-validated models using different combinations of DTI data from 927 HC subjects (18-94 years of age) and applied the models to the test sets including 648 patients with SZ (18-66 years of age), 185 patients with BD (18-64 years of age), and 990 HC subjects (17-68 years of age), estimating the brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results.

Results: Tenfold cross-validation revealed high accuracy for all models. Compared with HC subjects, the model including all feature sets significantly overestimated the age of patients with SZ (Cohen's d = -0.29) and patients with BD (Cohen's d = 0.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy-based models showed larger group differences than the models based on other DTI-derived metrics.

Conclusions: Brain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.
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http://dx.doi.org/10.1016/j.bpsc.2020.06.014DOI Listing
December 2020

Reliability of dopamine transporter PET measurements with [F]FE-PE2I in patients with Parkinson's disease.

EJNMMI Res 2020 Aug 14;10(1):95. Epub 2020 Aug 14.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm, Karolinska University Hospital, Stockholm, Sweden.

Background: Reliable quantification of dopamine transporter (DAT), a biomarker for Parkinson's disease (PD), is essential for diagnostic purposes as well as for evaluation of potential disease-modifying treatment. Due to degeneration of dopaminergic neurons and thus lower expected radioligand binding to DAT, higher measurement variability in PD patients might be expected than earlier reproducibility results in healthy controls. Therefore, we aimed to examine the test-retest properties of [F]FE-PE2I-PET in PD patients.

Methods: Nine patients with PD (Hoehn and Yahr stage < 3) were included (men/women 6/3; mean age 65.2 ± 6.8 years). Each patient underwent two [F]FE-PE2I-PET measurements within 7-28 days. The outcome measure was non-displaceable binding potential generated using wavelet-aided parametric imaging with cerebellum as reference region. We assessed test-retest performance using estimates of reliability and repeatability. Regions for primary analysis were caudate, putamen, ventral striatum, and substantia nigra. Exploratory analysis was performed for functional subdivisions of the striatum. We also compared the more vs. less affected side.

Results: [F]FE-PE2I showed absolute variability estimates of 5.3-7.6% in striatal regions and 11% in substantia nigra and ICCs of 0.74-0.97 (median 0.91). The absolute variability for functional striatal subdivisions was 6.0-9.6% and ICCs of 0.76-0.91 (median 0.91). The less affected substantia nigra exhibited greater consistency than the more affected side. According to power calculations based on the current sample size, DAT changes of 5-11% in the striatum and 28% in the substantia nigra can be detected with a power of 0.8 (p < 0.0125).

Conclusion: DAT-PET measurements with [F]FE-PE2I in PD patients showed good repeatability and reliability. The slightly lower reliability in the substantia nigra in patients may be explained by lower DAT density and smaller anatomical size. Power calculations suggest that [F]FE-PE2I PET is a suitable marker for longitudinal DAT decline in PD.

Trial Registration: EudraCT 2017-003327-29.
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http://dx.doi.org/10.1186/s13550-020-00676-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427674PMC
August 2020

The genetic architecture of human brainstem structures and their involvement in common brain disorders.

Nat Commun 2020 08 11;11(1):4016. Epub 2020 Aug 11.

NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

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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http://dx.doi.org/10.1038/s41467-020-17376-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7421944PMC
August 2020

Meta-analysis of the Glial Marker TSPO in Psychosis Revisited: Reconciling Inconclusive Findings of Patient-Control Differences.

Biol Psychiatry 2021 Feb 15;89(3):e5-e8. Epub 2020 Jul 15.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899168PMC
February 2021

Nondisplaceable Binding Is a Potential Confounding Factor in C-PBR28 Translocator Protein PET Studies.

J Nucl Med 2021 Mar 17;62(3):412-417. Epub 2020 Jul 17.

Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

The PET ligand C-PBR28 (-((2-(methoxy-C)-phenyl)methyl)--(6-phenoxy-3-pyridinyl)acetamide) binds to the 18-kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, V, is frequently the reported outcome measure. Since V is the sum of the ligand-specific distribution volume (V) and the nondisplaceable-binding distribution volume (V), differences in V across subjects and groups will have an impact on V Here, we used a recently developed method for simultaneous estimation of V (SIME) to disentangle contributions from V and V Data from 4 previously published C-PBR28 PET studies were included: before and after a lipopolysaccharide challenge (8 subjects), in alcohol use disorder (14 patients, 15 controls), in first-episode psychosis (16 patients, 16 controls), and in Parkinson disease (16 patients, 16 controls). In each dataset, regional V estimates were obtained with a standard 2-tissue-compartment model, and brain-wide V was estimated with SIME. V was then calculated as V - V V and V were then compared across groups, within each dataset. A lower V was found for individuals with alcohol-use disorder (34%, = 0.00084) and Parkinson disease (34%, = 0.0032) than in their corresponding controls. We found no difference in V between first-episode psychosis patients and their controls, and the administration of lipopolysaccharide did not change V Our findings suggest that in TSPO PET studies, nondisplaceable binding can differ between patient groups and conditions and should therefore be considered.
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http://dx.doi.org/10.2967/jnumed.120.243717DOI Listing
March 2021

Kinfitr - an open-source tool for reproducible PET modelling: validation and evaluation of test-retest reliability.

EJNMMI Res 2020 Jul 8;10(1):77. Epub 2020 Jul 8.

Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.

Background: In positron emission tomography (PET) imaging, binding is typically estimated by fitting pharmacokinetic models to the series of measurements of radioactivity in the target tissue following intravenous injection of a radioligand. However, there are multiple different models to choose from and numerous analytical decisions that must be made when modelling PET data. Therefore, it is important that analysis tools be adapted to the specific circumstances, and that analyses be documented in a transparent manner. Kinfitr, written in the open-source programming language R, is a tool developed for flexible and reproducible kinetic modelling of PET data, i.e. performing all steps using code which can be publicly shared in analysis notebooks. In this study, we compared outcomes obtained using kinfitr with those obtained using PMOD: a widely used commercial tool.

Results: Using previously collected test-retest data obtained with four different radioligands, a total of six different kinetic models were fitted to time-activity curves derived from different brain regions. We observed good correspondence between the two kinetic modelling tools both for binding estimates and for microparameters. Likewise, no substantial differences were observed in the test-retest reliability estimates between the two tools.

Conclusions: In summary, we showed excellent agreement between the open-source R package kinfitr, and the widely used commercial application PMOD. We, therefore, conclude that kinfitr is a valid and reliable tool for kinetic modelling of PET data.
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http://dx.doi.org/10.1186/s13550-020-00664-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343683PMC
July 2020

Dopamine D1 receptor availability is not associated with delusional ideation measures of psychosis proneness.

Schizophr Res 2020 08 29;222:175-184. Epub 2020 Jun 29.

Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-171 76 Stockholm, Sweden.

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 [C]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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http://dx.doi.org/10.1016/j.schres.2020.06.001DOI Listing
August 2020

CSF levels of synaptosomal-associated protein 25 and synaptotagmin-1 in first-episode psychosis subjects.

IBRO Rep 2020 Jun 13;8:136-142. Epub 2020 Apr 13.

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

Post-mortem studies consistently show evidence of reduced synaptic protein levels in patients with schizophrenia. Clinically high-risk subjects show a steeper decrease in grey matter thickness and modeling using patient-derived cells implicate excessive synaptic pruning during neurodevelopment as a part of the schizophrenia pathophysiology. However, it is unclear to what extent synapse elimination is present during various stages of the disease, which is of clinical importance as in a real-world setting most subjects received their first-episode psychosis (FEP) diagnosis not until their mid-twenties. In the present study, we measured cerebrospinal fluid (CSF) concentrations of the two pre-synaptic proteins synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1), both of which are increased in conditions of ongoing synaptic degeneration, in 44 FEP subjects (mean age 29.9 years) and 21 healthy controls (25.9 years) using immunoprecipitation mass spectrometry. Neither protein was found to differ between healthy controls and patients, and they showed no correlation with symptom ratings, cognitive performance or antipsychotic medication. Additional studies in high-risk subjects in the early prodromal phase will be needed to address if excessive synapse destruction occurs before the development of overt psychotic symptoms.
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http://dx.doi.org/10.1016/j.ibror.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262376PMC
June 2020

Synthesis and Preclinical Evaluation of 6-[F]Fluorine-α-methyl-l-tryptophan, a Novel PET Tracer for Measuring Tryptophan Uptake.

ACS Chem Neurosci 2020 06 5;11(12):1756-1761. Epub 2020 Jun 5.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Health Care Services, Region Stockholm, SE-171 76, Stockholm, Sweden.

The positron emission tomography (PET) radioligand α-[C]methyl-l-tryptophan ([C]AMT) has been used to assess tryptophan metabolism in cancer, epilepsy, migraine, and autism. Despite its extensive application, the utility of this tracer is currently hampered by the short half-life of the radionuclide used for its labeling (C, = 20.4 min). We herein report the design, synthesis, radiolabeling, and initial evaluation of a fluorine-18 (F, = 109.7 min) labeled analogue that is fluorinated in the 6-position of the aromatic ring ([F]6-F-AMTr). In a head-to-head comparison between [F]6-F-AMTr and [C]AMT in mice using PET, peak brain radioactivity, regional brain distribution, and kinetic profiles were similar between the two tracers. [F]6-F-AMTr was however not a substrate for IDO1 or TPH as determined in enzymatic assays. The brain uptake of the tracer is thus more likely related to LAT1 transport over the blood-brain barrier than metabolism along the serotonin or kynurenine pathways.
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http://dx.doi.org/10.1021/acschemneuro.0c00135DOI Listing
June 2020

Publisher Correction: Common brain disorders are associated with heritable patterns of apparent aging of the brain.

Nat Neurosci 2020 Feb;23(2):295

NORMENT, Division of Mental Health and Addiction Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41593-019-0553-6DOI Listing
February 2020

In response to the letter "[C]raclopride and extrastriatal binding to D2/3 receptors".

Neuroimage 2020 02 20;207:116371. Epub 2019 Nov 20.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Karolinska University Hospital, SE-171 76, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.neuroimage.2019.116371DOI Listing
February 2020

Clinical brain PET research must embrace multi-centre collaboration and data sharing or risk its demise.

Eur J Nucl Med Mol Imaging 2020 02 12;47(2):502-504. Epub 2019 Nov 12.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm County, Stockholm, Sweden.

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http://dx.doi.org/10.1007/s00259-019-04541-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974527PMC
February 2020

Common brain disorders are associated with heritable patterns of apparent aging of the brain.

Nat Neurosci 2019 10 24;22(10):1617-1623. Epub 2019 Sep 24.

NORMENT, Division of Mental Health and Addiction Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

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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http://dx.doi.org/10.1038/s41593-019-0471-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823048PMC
October 2019

Validity and reliability of extrastriatal [C]raclopride binding quantification in the living human brain.

Neuroimage 2019 11 29;202:116143. Epub 2019 Aug 29.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.

[C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (DR) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [C]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [C]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [C]raclopride: (i) To assess the validity of extrastriatal [C]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a DR antagonist. (ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BP) was quantified using the simplified reference tissue model with cerebellum as reference. Quetiapine dosing was associated with decrease in [C]raclopride BP in temporal cortex (18 ± 17% occupancy) and thalamus (20 ± 17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51 ± 4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [C]raclopride PET, quantified using cerebellum as reference, is not a suitable tool to measure DR in extrastriatal regions.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116143DOI Listing
November 2019

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [C]PBR28 HRRT PET study.

Eur J Nucl Med Mol Imaging 2019 Oct 30;46(11):2329-2338. Epub 2019 Jul 30.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm County, Stockholm, Sweden.

Purpose: The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [C]PBR28.

Methods: [C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (V) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts.

Results: There were significant positive correlations between age and V in the frontal and temporal cortex. BMI showed a significant negative correlation with V in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V. A subgroup analysis revealed a positive correlation between V and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects.

Conclusion: These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.
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http://dx.doi.org/10.1007/s00259-019-04403-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717599PMC
October 2019

Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk.

JAMA Psychiatry 2019 07;76(7):739-748

Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway.

Importance: Between-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.

Objectives: To 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 Participants: This 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 Measures: Mean 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.

Results: A 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 Relevance: This 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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http://dx.doi.org/10.1001/jamapsychiatry.2019.0257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583664PMC
July 2019

D1-Dopamine Receptor Availability in First-Episode Neuroleptic Naive Psychosis Patients.

Int J Neuropsychopharmacol 2019 07;22(7):415-425

Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.

Background: Positron emission tomography studies examining differences in D1-dopamine receptor binding between control subjects and patients with schizophrenia have been inconsistent, reporting higher, lower, and no difference in the frontal cortex. Exposure to antipsychotic medication has been suggested to be a likely source of this heterogeneity, and thus there is a need for studies of patients at early stages of the disorder who have not been exposed to such drugs.

Methods: Here, we compared 17 healthy control subjects and 18 first-episode neuroleptic naive patients with schizophrenia or schizophreniform psychosis using positron emission tomography and the D1-dopamine receptor radioligand [11C]SCH23390.

Results: We observed a statistically significant difference in the dorsolateral prefrontal cortex. Contrary to our expectations, patients had less D1-dopamine receptor availability with a moderate effect size. In a Bayesian analysis, we show that the data are over 50 times more likely to have occurred under the decrease as opposed to the increase hypothesis. This effect was not global, as our analysis showed that the null hypothesis was preferred over either hypothesis in the striatum.

Conclusions: This investigation represents the largest single sample of neuroleptic-naive patients examined for D1-dopamine receptor availability using PET and suggests a reduction of prefrontal D1-dopamine receptor density in the pathophysiology of schizophrenia. However, further work will be required to reach a consensus.
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http://dx.doi.org/10.1093/ijnp/pyz017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600463PMC
July 2019

Reproducible grey matter patterns index a multivariate, global alteration of brain structure in schizophrenia and bipolar disorder.

Transl Psychiatry 2019 01 17;9(1):12. Epub 2019 Jan 17.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients.
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http://dx.doi.org/10.1038/s41398-018-0225-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341112PMC
January 2019

Increased peripheral levels of TARC/CCL17 in first episode psychosis patients.

Schizophr Res 2019 08 3;210:221-227. Epub 2019 Jan 3.

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: Evidence for a link between the pathophysiology of schizophrenia and the immune system is mounting. Altered levels of chemokines in plasma have previously been reported in patients with schizophrenia under antipsychotic medication. Here we aimed to study both peripheral and central chemokine levels in drug-naïve or short-time medicated first episode psychosis (FEP) patients.

Method: We analyzed nine chemokines in plasma and CSF from 41 FEP patients and 22 healthy controls using electrochemiluminescence assay.

Results: In plasma four chemokines; TARC/CCL17, eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 and in CSF one chemokine; IP-10/CXCL10 showed reliable detection in >50% of the cases. FEP patients displayed increased levels of TARC/CCL17 in plasma compared to healthy controls, 89.6 (IQR 66.2-125.8) pg/mL compared to 48.6 (IQR 28.0-71.7) pg/mL (p = 0.001). The difference was not attributed to confounding factors. Plasma TARC/CCL17 was not associated with PANSS, CGI or GAF scores, neither with cognitive functions. The chemokines eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 in plasma and IP-10/CXCL10 in CSF did not differ between FEP patients and controls.

Conclusion: In line with a previous study showing that chronic patients with schizophrenia display increased plasma TARC/CCL17 levels, we here found an elevation in FEP patients suggesting a role of TARC/CCL17 in early stages of schizophrenia. The exact mechanism of this involvement is still unknown and future longitudinal studies as well as studies of central and peripheral chemokine levels would be of great interest.
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http://dx.doi.org/10.1016/j.schres.2018.12.033DOI Listing
August 2019

Trait impulsivity is not related to post-commissural putamen volumes: A replication study in healthy men.

PLoS One 2018 20;13(12):e0209584. Epub 2018 Dec 20.

Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE, Stockholm, Sweden.

High levels of trait impulsivity are considered a risk factor for substance abuse and drug addiction. We recently found that non-planning trait impulsivity was negatively correlated with post-commissural putamen volumes in men, but not women, using the Karolinska Scales of Personality (KSP). Here, we attempted to replicate this finding in an independent sample using an updated version of the KSP: the Swedish Universities Scales of Personality (SSP). Data from 88 healthy male participants (Mean Age: 28.16±3.34), who provided structural T1-weighted magnetic resonance images (MRIs) and self-reported SSP impulsivity scores, were analyzed. Striatal sub-region volumes were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Contrary to our previous findings trait impulsivity measured using SSP was not a significant predictor of post-commissural putamen volumes (β = .14, df = 84, p = .94). A replication Bayes Factors analysis strongly supported this null result. Consistent with our previous findings, secondary exploratory analyses found no relationship between ventral striatum volumes and SSP trait impulsivity (β = -.05, df = 84, p = .28). An exploratory analysis of the other striatal compartments showed that there were no significant associations with trait impulsivity. While we could not replicate our previous findings in the current sample, we believe this work will aide future studies aimed at establishing meaningful brain biomarkers for addiction vulnerability in healthy humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209584PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301704PMC
May 2019

Accuracy and reliability of [C]PBR28 specific binding estimated without the use of a reference region.

Neuroimage 2019 03 27;188:102-110. Epub 2018 Nov 27.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm County Council, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.

[C]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [C]PBR28 binding and the most common outcome measure is the total distribution volume (V). Notably, V reflects both specific binding and non-displaceable binding. Therefore, estimates of specific binding, such as binding potential (e.g. BP) and specific distribution volume (V) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these outcome measures are obtainable for [C]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of the non-displaceable distribution volume (V), which can subsequently be used to improve the estimation of BP and V. In this study we evaluated the accuracy of SIME-derived V, and the reliability of resulting estimates of specific binding for [C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments, based on data from 54 unique [C]PBR28 examinations, showed that V values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge (n = 5) showed that SIME provided V values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data (n = 11) showed that SIME-derived V values exhibited good reliability and precision, while larger variability was observed in SIME-derived BP values. The results support the use of SIME for quantifying specific binding of [C]PBR28, and suggest that V can be used in complement to the conventional outcome measure V. Additional studies in patient cohorts are warranted.
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http://dx.doi.org/10.1016/j.neuroimage.2018.11.020DOI Listing
March 2019

Test-retest reliability and convergent validity of (R)-[C]PK11195 outcome measures without arterial input function.

EJNMMI Res 2018 Nov 29;8(1):102. Epub 2018 Nov 29.

Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-171 76, Stockholm, Sweden.

Purpose: The PET radioligand (R)-[C]PK11195 is used to quantify the 18-kDa translocator protein (TSPO), a marker for glial activation. Since there is no brain region devoid of TSPO, an arterial input function (AIF) is ideally required for quantification of binding. However, obtaining an AIF is experimentally demanding, is sometimes uncomfortable for participants, and can introduce additional measurement error during quantification. The objective of this study was to perform an evaluation of the test-retest reliability and convergent validity of techniques used for quantifying (R)-[C]PK11195 binding without an AIF in clinical studies.

Methods: Data from six healthy individuals who participated in two PET examinations, 6 weeks apart, were analyzed. Regional non-displaceable binding potential (BP) values were calculated using the simplified reference tissue model, with either cerebellum as reference region or a reference input derived using supervised cluster analysis (SVCA). Standardized uptake values (SUVs) were estimated for the time interval of 40-60 min.

Results: Test-retest reliability for BP estimates were poor (80% of ICCs < 0.5). BP estimates derived without an AIF were not correlated with BP, total or specific distribution volume from the 2TCM using an AIF (all R < 12%). SUVs showed moderate reliability but no correlation to any other outcome measure.

Conclusions: Caution is warranted when interpreting patient-control comparisons employing (R)-[C]PK11195 outcome measures obtained without an AIF.
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http://dx.doi.org/10.1186/s13550-018-0455-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265355PMC
November 2018

Serotonin 5-HT receptor binding and self-transcendence in healthy control subjects-a replication study using Bayesian hypothesis testing.

PeerJ 2018 16;6:e5790. Epub 2018 Nov 16.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.

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-HT 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-HT receptor binding potential (BP) was examined in 50 healthy male subjects using PET with the radioligand [C]WAY100635. 5-HTavailability was calculated using the simplified reference tissue model (SRTM) yielding regional BP. ST and SA were measured using the Temperament and Character Inventory (TCI) questionnaire. Correlations between ST/SA scores and 5-HTBP 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-HT receptor binding and ST/SA scores. Rather, five of six replication BFs provided moderate to strong evidence for no association between 5-HT 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-HT 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 -values, suggesting that this approach may be advantageous for analysis of molecular imaging data.
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http://dx.doi.org/10.7717/peerj.5790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241390PMC
November 2018