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  • 1.
    Barth, Claudia
    et al.
    Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Kelly, Sinead
    Kings Coll London, Dept Psychosis Studies, London, England..
    Nerland, Stener
    Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Jahanshad, Neda
    Univ Southern Calif, Mark Mary Stevens Neuroimaging Informat Inst, Keck Sch Med, Imaging Genet Ctr, Marina Del Rey, CA USA..
    Alloza, Clara
    Hosp Gen Univ Gregorio Maranon, Inst Psychiat & Mental Hlth, Dept Child & Adolescent Psychiat, IiSGM, Madrid, Spain..
    Ambrogi, Sonia
    Santa Lucia Fdn IRCCS, Lab Neuropsychiat, Rome, Italy..
    Andreassen, Ole A.
    Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Andreou, Dimitrios
    Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway.;Karolinska Inst Stockholm Hlth Care Serv, Dept Clin Neurosci, Ctr Psychiat Res, Stockholm, Sweden..
    Arango, Celso
    Hosp Gen Univ Gregorio Maranon, Inst Psychiat & Mental Hlth, Dept Child & Adolescent Psychiat, IiSGM, Madrid, Spain.;Univ Complutense, Sch Med, Madrid, Spain..
    Baeza, Inmaculada
    Univ Barcelona, August Pi Sunyer Biomed Res Inst IDIBAPS, Dept Child & Adolescent Psychiat & Psychol, Inst Neurosci, 2017SGR881, Barcelona, Spain..
    Banaj, Nerisa
    Santa Lucia Fdn IRCCS, Lab Neuropsychiat, Rome, Italy..
    Bearden, Carrie E.
    UCLA, Semel Inst Neurosci & Human Behav, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA.;UCLA, Dept Psychol, Los Angeles, CA USA..
    Berk, Michael
    Deakin Univ, Inst Mental & Phys Hlth & Clin Translat, Sch Med, Barwon Hlth, Geelong, Vic, Australia..
    Bohman, Hannes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Barn- och ungdomspsykiatri. Karolinska Inst, Dept Clin Sci & Educ Sodersjukhuset, Stockholm, Sweden..
    Castro-Fornieles, Josefina
    Univ Barcelona, August Pi Sunyer Biomed Res Inst IDIBAPS, Dept Child & Adolescent Psychiat & Psychol, Inst Neurosci, 2017SGR881, Barcelona, Spain..
    Chye, Yann
    Monash Univ, Turner Inst Brain & Mental Hlth & Sch Psychol Sci, Melbourne, Vic, Australia..
    Crespo-Facorro, Benedicto
    Univ Seville, Hosp Univ Virgen Rocio, Dept Psychiat, CIBERSAM, Seville, Spain..
    de la Serna, Elena
    Univ Barcelona, August Pi Sunyer Biomed Res Inst IDIBAPS, Dept Child & Adolescent Psychiat & Psychol, Inst Neurosci, 2017SGR881, Barcelona, Spain..
    Diaz-Caneja, Covadonga M.
    Hosp Gen Univ Gregorio Maranon, Inst Psychiat & Mental Hlth, Dept Child & Adolescent Psychiat, IiSGM, Madrid, Spain.;Univ Complutense, Sch Med, Madrid, Spain..
    Gurholt, Tiril P.
    Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Hegarty, Catherine E.
    UCLA, Dept Psychol, Los Angeles, CA USA..
    James, Anthony
    Warneford Hosp, Highfield Unit, Oxford, England.;Warneford Hosp, Highfield Unit, Oxford, England..
    Janssen, Joost
    Hosp Gen Univ Gregorio Maranon, Inst Psychiat & Mental Hlth, Dept Child & Adolescent Psychiat, IiSGM, Madrid, Spain..
    Johannessen, Cecilie
    Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Jönsson, Erik G.
    Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway.;Karolinska Inst Stockholm Hlth Care Serv, Dept Clin Neurosci, Ctr Psychiat Res, Stockholm, Sweden..
    Karlsgodt, Katherine H.
    UCLA, Semel Inst Neurosci & Human Behav, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA.;UCLA, Dept Psychol, Los Angeles, CA USA..
    Kochunov, Peter
    Univ Oxford, Dept Psychiat, Oxford, England..
    Lois, Noemi G.
    Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Sch Med, Baltimore, MA USA..
    Lundberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Barn- och ungdomspsykiatri. Karolinska Inst, Dept Clin Sci & Educ Sodersjukhuset, Stockholm, Sweden..
    Myhre, Anne M.
    Oslo Univ Hosp, Div Mental Hlth & Addict, Sect Child & Adolescent Mental Hlth Res, Oslo, Norway..
    Pascual-Diaz, Sauel
    Univ Barcelona, August Pi Sunyer Biomed Res Inst IDIBAPS, Magnet Resonance Imaging Core Facil, Barcelona, Spain..
    Piras, Fabrizio
    Santa Lucia Fdn IRCCS, Lab Neuropsychiat, Rome, Italy..
    Smelror, Runar E.
    Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Spalletta, Gianfranco
    Santa Lucia Fdn IRCCS, Lab Neuropsychiat, Rome, Italy.;Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX USA..
    Stokkan, Therese S.
    Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Sugranyes, Gisela
    Univ Barcelona, August Pi Sunyer Biomed Res Inst IDIBAPS, Dept Child & Adolescent Psychiat & Psychol, Inst Neurosci, 2017SGR881, Barcelona, Spain..
    Suo, Chao
    Monash Univ, Turner Inst Brain & Mental Hlth & Sch Psychol Sci, Melbourne, Vic, Australia..
    Thomopoulos, Sophia I.
    Univ Southern Calif, Mark Mary Stevens Neuroimaging Informat Inst, Keck Sch Med, Imaging Genet Ctr, Marina Del Rey, CA USA..
    Tordesillas-Gutierrez, Diana
    Marques Valdecilla Univ Hosp, Valdecilla Biomed Res Inst IDIVAL, Dept Radiol, Santander, Spain.;Inst Fis Cantabria UC CSIC, Advanced Comp & Sci, Santander, Spain..
    Vecchio, Daniela
    Santa Lucia Fdn IRCCS, Lab Neuropsychiat, Rome, Italy..
    Wedervang-Resell, Kirsten
    Oslo Univ Hosp, Div Mental Hlth & Addict, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Wortinger, Laura A.
    Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway..
    Thompson, Paul M.
    Univ Southern Calif, Mark Mary Stevens Neuroimaging Informat Inst, Keck Sch Med, Imaging Genet Ctr, Marina Del Rey, CA USA..
    Agartz, Ingrid
    Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway.;Karolinska Inst Stockholm Hlth Care Serv, Dept Clin Neurosci, Ctr Psychiat Res, Stockholm, Sweden..
    In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis2023Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, s. 1159-1169Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age=16.6 years, interquartile range (IQR)=2.14, 46.4% females) and 265 adolescent healthy controls (median age=16.2 years, IQR=2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d=0.37), posterior corona radiata (d=0.32), and superior fronto-occipital fasciculus (d=0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

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    FULLTEXT01
  • 2.
    Borg, J.
    et al.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Cervenka, Simon
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Kuja-Halkola, R.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Matheson, G. J.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Jonsson, E. G.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Univ Oslo, Psychiat Sect, Inst Clin Med, NORMENT,KG Jebsen Ctr Psychosis Res, Oslo, Norway..
    Lichtenstein, P.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Henningsson, S.
    Copenhagen Univ Hosp, Danish Res Ctr Magnet Resonance, Hvidovre, Denmark..
    Ichimiya, T.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Nippon Med Sch, Dept Neuropsychiat, Tokyo, Japan..
    Larsson, H.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Stenkrona, P.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Halldin, C.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Farde, L.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, AstraZeneca Translat Sci Ctr, Stockholm, Sweden..
    Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain2016Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, nr 8, s. 1077-1084Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [C-11]raclopride binding to the D-2- and D-3-dopamine receptor and [C-11]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D-2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D-2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

  • 3. Chiotis, K
    et al.
    Saint-Aubert, L
    Rodriguez-Vieitez, E
    Leuzy, A
    Almkvist, O
    Savitcheva, I
    Jonasson, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wall, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Nordberg, A
    Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia2018Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, nr 7, s. 1666-1673Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [(18)F]THK5317 (tau deposition) and [(18)F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [(11)C]PIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [(18)F]THK5317 retention over time, in contrast to significant decreases in [(18)F]FDG uptake in temporoparietal areas. The pattern of changes in [(18)F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [(18)F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [(18)F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [(11)C]PIB scan, high [(18)F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [(18)F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.Molecular Psychiatry advance online publication, 16 May 2017; doi:10.1038/mp.2017.108.

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    fulltext
  • 4.
    Chiotis, Konstantinos
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Nordberg Translat Mol Imaging Lab, Div Clin Geriatr,Ctr Alzheimer Res, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Neurol, Stockholm, Sweden..
    Savitcheva, Irina
    Karolinska Univ Hosp, Med Radiat Phys & Nucl Med, Stockholm, Sweden..
    Poulakis, Konstantinos
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Westman Neuroimaging Grp,Div Clin Geriatr, Stockholm, Sweden..
    Saint-Aubert, Laure
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Nordberg Translat Mol Imaging Lab, Div Clin Geriatr,Ctr Alzheimer Res, Stockholm, Sweden.;Univ Toulouse, Toulouse NeuroImaging Ctr, INSERM, UPS, Toulouse, France..
    Wall, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Nordberg Translat Mol Imaging Lab, Div Clin Geriatr,Ctr Alzheimer Res, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Aging, Stockholm, Sweden..
    [F-18]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer's disease2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 10, s. 5875-5887Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer's disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [F-18]THK5317, [C-11]PIB and [F-18]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56). In total, 11 patients declined cognitively over time, while 9 remained cognitively stable. The accuracy of baseline [F-18]THK5317 binding in temporal areas was excellent at predicting future cognitive decline (area under the receiver operating curve 0.84-1.00) and the biomarker levels were strongly associated with the rate of cognitive decline (beta estimate -33.67 to -31.02,p < 0.05). The predictive accuracy of the other baseline biomarkers was poor (area under the receiver operating curve 0.58-0.77) and their levels were not associated with the rate of cognitive decline (beta estimate -4.64 to 15.78,p > 0.05). Baseline [F-18]THK5317 binding and CSF tau levels were more strongly associated with the MMSE score at follow-up than at baseline (p < 0.05). These findings support a temporal dissociation between tau deposition and cognitive impairment, and suggest that [F-18]THK5317 predicts future cognitive decline better than other biomarkers. The use of imaging markers for tau pathology could prove useful for clinical prognostic assessment and screening before inclusion in relevant clinical trials.

    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 5.
    Clifton, N.E.
    et al.
    Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
    Pocklington, A.J.
    MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
    Scholz, Birger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Rees, E.
    MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
    Walters, J.T.R.
    MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
    Kirov, G.
    MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
    O'Donovan, M.C.
    MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
    Owen, M.J.
    MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
    Wilkinson, L.S.
    School of Psychology, Cardiff University, Cardiff, UK.
    Thomas, K.L.
    School of Biosciences, Cardiff University, Cardiff, UK.
    Hall, J.
    Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
    Schizophrenia copy number variants and associative learning2017Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, s. 178-182Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder.

  • 6.
    Collste, K.
    et al.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Plaven-Sigray, P.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Fatouros-Bergman, H.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Victorsson, P.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Schain, M.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Columbia Univ, Dept Psychiat, Mol Imaging & Neuropathol Div, New York, NY USA..
    Forsberg, A.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Amini, N.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Aeinehband, S.
    Karolinska Univ Hosp, Karolinska Inst, Dept Clin Neurosci, Neuroimmunol Unit, Stockholm, Sweden..
    Erhardt, S.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Halldin, C.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Flyckt, L.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Astrazeneca PET Sci Ctr, Personalised Healthcare & Biomarkers, Stockholm, Sweden..
    Farde, L.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Cervenka, Simon
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Univ Cambridge, Dept Psychiat, Cambridge, England..
    Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [C-11]PBR282017Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, nr 6, s. 850-856Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [C-11]PBR28. Gray matter (GM) volume of distribution (V-T) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [C-11]PBR28 binding, and gender. There was a significant reduction of [C-11]PBR28 V-T in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM V-T and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

  • 7. Cornelis, M C
    et al.
    Byrne, E M
    Esko, T
    Nalls, M A
    Ganna, A
    Paynter, N
    Monda, K L
    Amin, N
    Fischer, K
    Renstrom, F
    Ngwa, J S
    Huikari, V
    Cavadino, A
    Nolte, I M
    Teumer, A
    Yu, K
    Marques-Vidal, P
    Rawal, R
    Manichaikul, A
    Wojczynski, M K
    Vink, J M
    Zhao, J H
    Burlutsky, G
    Lahti, J
    Mikkilä, V
    Lemaitre, R N
    Eriksson, J
    Musani, S K
    Tanaka, T
    Geller, F
    Luan, J
    Hui, J
    Mägi, R
    Dimitriou, M
    Garcia, M E
    Ho, W-K
    Wright, M J
    Rose, L M
    Magnusson, P K E
    Pedersen, N L
    Couper, D
    Oostra, B A
    Hofman, A
    Ikram, M A
    Tiemeier, H W
    Uitterlinden, A G
    van Rooij, F J A
    Barroso, I
    Johansson, I
    Xue, L
    Kaakinen, M
    Milani, L
    Power, C
    Snieder, H
    Stolk, R P
    Baumeister, S E
    Biffar, R
    Gu, F
    Bastardot, F
    Kutalik, Z
    Jacobs, D R
    Forouhi, N G
    Mihailov, E
    Lind, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, C
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Morris, A
    Jensen, M
    Khaw, K-T
    Luben, R N
    Wang, J J
    Männistö, S
    Perälä, M-M
    Kähönen, M
    Lehtimäki, T
    Viikari, J
    Mozaffarian, D
    Mukamal, K
    Psaty, B M
    Döring, A
    Heath, A C
    Montgomery, G W
    Dahmen, N
    Carithers, T
    Tucker, K L
    Ferrucci, L
    Boyd, H A
    Melbye, M
    Treur, J L
    Mellström, D
    Hottenga, J J
    Prokopenko, I
    Tönjes, A
    Deloukas, P
    Kanoni, S
    Lorentzon, M
    Houston, D K
    Liu, Y
    Danesh, J
    Rasheed, A
    Mason, M A
    Zonderman, A B
    Franke, L
    Kristal, B S
    Karjalainen, J
    Reed, D R
    Westra, H-J
    Evans, M K
    Saleheen, D
    Harris, T B
    Dedoussis, G
    Curhan, G
    Stumvoll, M
    Beilby, J
    Pasquale, L R
    Feenstra, B
    Bandinelli, S
    Ordovas, J M
    Chan, A T
    Peters, U
    Ohlsson, C
    Gieger, C
    Martin, N G
    Waldenberger, M
    Siscovick, D S
    Raitakari, O
    Eriksson, J G
    Mitchell, P
    Hunter, D J
    Kraft, P
    Rimm, E B
    Boomsma, D I
    Borecki, I B
    Loos, R J F
    Wareham, N J
    Vollenweider, P
    Caporaso, N
    Grabe, H J
    Neuhouser, M L
    Wolffenbuttel, B H R
    Hu, F B
    Hyppönen, E
    Järvelin, M-R
    Cupples, L A
    Franks, P W
    Ridker, P M
    van Duijn, C M
    Heiss, G
    Metspalu, A
    North, K E
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nettleton, J A
    van Dam, R M
    Chasman, D I
    Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption2015Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 20, nr 5, s. 647-656Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

  • 8.
    Culverhouse, R. C.
    et al.
    Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA..
    Saccone, N. L.
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA..
    Horton, A. C.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Ma, Y.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Anstey, K. J.
    Australian Natl Univ, Ctr Res Ageing Hlth & Wellbeing, Canberra, ACT, Australia..
    Banaschewski, T.
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, Mannheim, Germany..
    Burmeister, M.
    Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Cohen-Woods, S.
    Flinders Univ S Australia, Sch Psychol, Fac Social & Behav Sci, Adelaide, SA, Australia..
    Etain, B.
    Univ Paris Diderot, Sorbonne Paris Cite, UMR S 1144, Paris, France.;AP HP, Grp St Louis Lariboisiere F, Paris, France.;INSERM, U1144, Paris, France..
    Fisher, H. L.
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London, England..
    Goldman, N.
    Princeton Univ, Off Populat Res, Princeton, NJ 08544 USA..
    Guillaume, S.
    Univ Montpellier, Montpellier, France.;INSERM, Neuropsychiat U1061, Montpellier, France.;CHU Montpellier, Dept Emergency Psychiat & Acute Care, Montpellier, France..
    Horwood, J.
    Univ Otago Christchurch, Dept Psychol Med, Christchurch, New Zealand..
    Juhasz, G.
    Semmelweis Univ, Hungarian Acad Sci, MTA SE NAP Genet Brain Imaging Migraine Res Grp B, Budapest, Hungary.;Semmelweis Univ, Dept Pharmacodynam, Budapest, Hungary.;Univ Manchester, Neurosci & Psychiat Unit, Manchester, Lancs, England.;Semmelweis Univ, NAP A SE New Antidepressant Target Res Grp, Budapest, Hungary..
    Lester, K. J.
    Univ Sussex, Sch Psychol, Brighton, E Sussex, England..
    Mandelli, L.
    Univ Bologna, Dept Biomed & NeuroMotor Sci, Bologna, Italy..
    Middeldorp, C. M.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Olie, E.
    Univ Montpellier, Montpellier, France.;INSERM, Neuropsychiat U1061, Montpellier, France.;CHU Montpellier, Dept Emergency Psychiat & Acute Care, Montpellier, France..
    Villafuerte, S.
    Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA..
    Air, T. M.
    Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia..
    Araya, R.
    London Sch Hyg & Trop Med, Ctr Global Mental Hlth, London, England..
    Bowes, L.
    Univ Oxford, Dept Expt Psychol, Oxford, England..
    Burns, R.
    Australian Natl Univ, Ctr Res Ageing Hlth & Wellbeing, Canberra, ACT, Australia..
    Byrne, E. M.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Coffey, C.
    Murdoch Childrens Res Inst, Ctr Adolescent Hlth, Melbourne, Vic, Australia..
    Coventry, W. L.
    Univ New England, Discipline Psychol, Armidale, NSW, Australia..
    Gawronski, K. A. B.
    Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Glei, D.
    Georgetown Univ, Ctr Populat & Hlth, Washington, DC USA..
    Hatzimanolis, A.
    Univ Athens, Sch Med, Eginit Hosp, Dept Psychiat, Athens, Greece.;Theodor Theohari Cozzika Fdn, Neurobiol Res Inst, Athens, Greece..
    Hottenga, J-J
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;VU Med Ctr Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Jaussent, I.
    INSERM, Neuropsychiat U1061, Montpellier, France..
    Jawahar, C.
    Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia..
    Jennen-Steinmetz, C.
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Biostat, Mannheim, Germany..
    Kramer, J. R.
    Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA..
    Lajnef, M.
    INSERM, U955, Creteil, France..
    Little, K.
    Murdoch Childrens Res Inst, Melbourne, Vic, Australia.;Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia.;Univ Melbourne, Sch Psychol Sci, Melbourne, Vic, Australia..
    zu Schwabedissen, H. M.
    Univ Basel, Dept Pharmaceut Sci, Biopharm, Basel, Switzerland..
    Nauck, M.
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany..
    Nederhof, E.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Petschner, P.
    Semmelweis Univ, Dept Pharmacodynam, Budapest, Hungary.;Semmelweis Univ, NAP A SE New Antidepressant Target Res Grp, Budapest, Hungary.;Semmelweis Univ, Hungarian Acad Sci, MTA SE Neuropsychopharmacol & Neurochem Res Grp, Budapest, Hungary..
    Peyrot, W. J.
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;GGZ InGeest, Amsterdam, Netherlands..
    Schwahn, C.
    Univ Med Greifswald, Dept Prosthet Dent Gerostomatol & Dent Mat, Greifswald, Germany..
    Sinnamon, G.
    Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia..
    Stacey, D.
    Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia..
    Tian, Y.
    Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA..
    Toben, C.
    Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia..
    Van der Auwera, S.
    Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany..
    Wainwright, N.
    Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge, England..
    Wang, J-C
    Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA..
    Willemsen, G.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;VU Med Ctr Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Anderson, I. M.
    Univ Manchester, Neurosci & Psychiat Unit, Manchester, Lancs, England.;Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England..
    Arolt, V.
    Univ Munster, Dept Psychiat & Psychotherapy, Munster, Germany..
    Åslund, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås. Västmanland Cty Hosp Västerås, Västerås, Sweden..
    Bagdy, G.
    Semmelweis Univ, Dept Pharmacodynam, Budapest, Hungary.;Semmelweis Univ, NAP A SE New Antidepressant Target Res Grp, Budapest, Hungary.;Semmelweis Univ, Hungarian Acad Sci, MTA SE Neuropsychopharmacol & Neurochem Res Grp, Budapest, Hungary..
    Baune, B. T.
    Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia..
    Bellivier, F.
    Univ Paris Diderot, Sorbonne Paris Cite, UMR S 1144, Paris, France.;AP HP, Grp St Louis Lariboisiere F, Paris, France.;INSERM, U1144, Paris, France..
    Boomsma, D. I.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;VU Med Ctr Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Courtet, P.
    Univ Montpellier, Montpellier, France.;INSERM, Neuropsychiat U1061, Montpellier, France.;CHU Montpellier, Dept Emergency Psychiat & Acute Care, Montpellier, France..
    Dannlowski, U.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;VU Med Ctr Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.;Univ Munster, Dept Psychiat & Psychotherapy, Munster, Germany..
    de Geus, E. J. C.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;VU Med Ctr Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Deakin, J. F. W.
    Univ Manchester, Neurosci & Psychiat Unit, Manchester, Lancs, England.;Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England..
    Easteal, S.
    Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT, Australia..
    Eley, T.
    Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England..
    Fergusson, D. M.
    Univ Otago Christchurch, Dept Psychol Med, Christchurch, New Zealand..
    Goate, A. M.
    Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA..
    Gonda, X.
    Semmelweis Univ, Dept Pharmacodynam, Budapest, Hungary.;Semmelweis Univ, NAP A SE New Antidepressant Target Res Grp, Budapest, Hungary.;Semmelweis Univ, Hungarian Acad Sci, MTA SE Neuropsychopharmacol & Neurochem Res Grp, Budapest, Hungary.;Semmelweis Univ, Kutvolgyi Clin Ctr, Dept Psychiat & Psychotherapy, Budapest, Hungary..
    Grabe, H. J.
    Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany..
    Holzman, C.
    Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA..
    Johnson, E. O.
    RTI Int, Fellow Program, Res Triangle Pk, NC USA.;RTI Int, Behav Hlth & Criminal Justice Div, Res Triangle Pk, NC USA..
    Kennedy, M.
    Univ Otago, Dept Pathol, Christchurch, New Zealand..
    Laucht, M.
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, Mannheim, Germany..
    Martin, N. G.
    QIMR Berghofer, Genet Epidemiol, Brisbane, Qld, Australia..
    Munafo, M. R.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.;Univ Bristol, Sch Expt Psychol, UK Ctr Tobacco & Alcohol Studies, Bristol, Avon, England..
    Nillson, Kent W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås. Västmanland Cty Hosp Västerås, Västerås, Sweden..
    Oldehinkel, A. J.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Olsson, C. A.
    Deakin Univ Geelong, Ctr Social & Early Emot Dev, Sch Psychol, Fac Hlth, Burwood, Vic, Australia.;Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia.;Univ Melbourne, Sch Psychol Sci, Melbourne, Vic, Australia.;Murdoch Childrens Res Inst, Ctr Adolescent Hlth, Melbourne, Vic, Australia..
    Ormel, J.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Otte, C.
    Charite, Klin Psychiat & Psychotherapie Campus Benjamin Fr, Berlin, Germany..
    Patton, G. C.
    Univ Melbourne, Murdoch Childrens Res Inst, Dept Paediat, Melbourne, Vic, Australia..
    Penninx, B. W. J. H.
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;GGZ InGeest, Amsterdam, Netherlands..
    Ritchie, K.
    INSERM, Neuropsychiat U1061, Montpellier, France..
    Sarchiapone, M.
    Univ Molise, Dept Hlth Sci, Campobasso, Italy..
    Scheid, J. M.
    Michigan State Univ, Dept Psychiat, E Lansing, MI 48824 USA..
    Serretti, A.
    Univ Bologna, Dept Biomed & NeuroMotor Sci, Bologna, Italy..
    Smit, J. H.
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;GGZ InGeest, Amsterdam, Netherlands..
    Stefanis, N. C.
    Univ Athens, Sch Med, Eginit Hosp, Dept Psychiat, Athens, Greece.;Theodor Theohari Cozzika Fdn, Neurobiol Res Inst, Athens, Greece..
    Surtees, P. G.
    Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge, England..
    Voelzke, H.
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Weinstein, M.
    Georgetown Univ, Ctr Populat & Hlth, Washington, DC USA..
    Whooley, M.
    Vet Affairs Hlth Care Syst, San Francisco, CA USA.;Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Nurnberger, J. I., Jr.
    Indiana Univ Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Dept Med & Mol Genet, Inst Psychiat Res, Indianapolis, IN 46202 USA..
    Breslau, N.
    Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA..
    Bierut, L. J.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression2018Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, nr 1, s. 133-142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

  • 9. Dodman, N. H.
    et al.
    Karlsson, E. K.
    Moon-Fanelli, A.
    Galdzicka, M.
    Perloski, M.
    Shuster, L.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ginns, E. I.
    A canine chromosome 7 locus confers compulsive disorder susceptibility2010Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 15, nr 1, s. 8-10Artikel i tidskrift (Refereegranskat)
  • 10. Fernandes, C.
    et al.
    Grayton, H.
    Poston, L.
    Samuelsson, A-M
    Taylor, P. D.
    Collier, D. A.
    Rodriguez, Alejandro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Prenatal exposure to maternal obesity leads to hyperactivity in offspring2012Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 17, nr 12, s. 1159-1160Artikel i tidskrift (Refereegranskat)
  • 11.
    Frick, Anderas
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Åhs, Fredrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Palmquist, Åsa M.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Pissiota, A.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Wallenquist, Ulrika
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Fernandez, Manuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Jonasson, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Frans, Örjan
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    von Knorring, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Alterations in the serotonergic and substance P systems in posttraumatic stress disorder2016Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, nr 10, s. 1323-1323Artikel i tidskrift (Övrigt vetenskapligt)
  • 12.
    Frick, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Psykiatri.
    Björkstrand, Johannes
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Lund Univ, Dept Psychol, Lund, Sweden..
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Eriksson, Allison
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrisk och reproduktiv hälsoforskning.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Åhs, Fredrik
    Mid Sweden Univ, Dept Psychol & Social Work, Östersund, Sweden..
    Dopamine and fear memory formation in the human amygdala2022Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, nr 3, s. 1704-1711Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

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  • 13.
    Frick, Andreas
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Åhs, Fredrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Michelgård Palmquist, Åsa
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Pissiota, Anna
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Wallenquist, Ulrika
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Fernandez, Manuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Jonasson, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Frans, Örjan
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    von Knorring, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study2016Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, nr 10, s. 1400-1407Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [(11)C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.

  • 14. Groenewold, Nynke A.
    et al.
    Bas-Hoogendam, Janna Marie
    Amod, Alyssa R.
    Laansma, Max A.
    Van Velzen, Laura S.
    Aghajani, Moji
    Hilbert, Kevin
    Oh, Hyuntaek
    Salas, Ramiro
    Jackowski, Andrea P.
    Pan, Pedro M.
    Salum, Giovanni A.
    Blair, James R.
    Blair, Karina S.
    Hirsch, Joy
    Pantazatos, Spiro P.
    Schneier, Franklin R.
    Talati, Ardesheer
    Roelofs, Karin
    Volman, Inge
    Blanco-Hinojo, Laura
    Cardoner, Narcís
    Pujol, Jesus
    Beesdo-Baum, Katja
    Ching, Christopher R. K.
    Thomopoulos, Sophia I.
    Jansen, Andreas
    Kircher, Tilo
    Krug, Axel
    Nenadić, Igor
    Stein, Frederike
    Dannlowski, Udo
    Grotegerd, Dominik
    Lemke, Hannah
    Meinert, Susanne
    Winter, Alexandra
    Erb, Michael
    Kreifelts, Benjamin
    Gong, Qiyong
    Lui, Su
    Zhu, Fei
    Mwangi, Benson
    Soares, Jair C.
    Wu, Mon-Ju
    Bayram, Ali
    Canli, Mesut
    Tükel, Raşit
    Westenberg, P. Michiel
    Heeren, Alexandre
    Cremers, Henk R.
    Hofmann, David
    Straube, Thomas
    Doruyter, Alexander G. G.
    Lochner, Christine
    Peterburs, Jutta
    Van Tol, Marie-José
    Gur, Raquel E.
    Kaczkurkin, Antonia N.
    Larsen, Bart
    Satterthwaite, Theodore D.
    Filippi, Courtney A.
    Gold, Andrea L.
    Harrewijn, Anita
    Zugman, André
    Bülow, Robin
    Grabe, Hans J.
    Völzke, Henry
    Wittfeld, Katharina
    Böhnlein, Joscha
    Dohm, Katharina
    Kugel, Harald
    Schrammen, Elisabeth
    Zwanzger, Peter
    Leehr, Elisabeth J.
    Sindermann, Lisa
    Ball, Tali M.
    Fonzo, Gregory A.
    Paulus, Martin P.
    Simmons, Alan
    Stein, Murray B.
    Klumpp, Heide
    Phan, K. Luan
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Månsson, Kristoffer N. T.
    Manzouri, Amirhossein
    Avery, Suzanne N.
    Blackford, Jennifer Urbano
    Clauss, Jacqueline A.
    Feola, Brandee
    Harper, Jennifer C.
    Sylvester, Chad M.
    Lueken, Ulrike
    Veltman, Dick J.
    Winkler, Anderson M.
    Jahanshad, Neda
    Pine, Daniel S.
    Thompson, Paul M.
    Stein, Dan J.
    Van der Wee, Nic J. A.
    Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group2023Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, nr 3, s. 1079-1089Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = −0.077, pFWE = 0.037; right: d = −0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = −0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = −0.141, pFWE < 0.001; right: d = −0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

  • 15.
    Hampel, Harald
    et al.
    Eisai Inc, Neurol Business Grp, Woodcliff Lake, NJ 07677 USA..
    Hardy, John
    UCL, UK Dementia Res Inst, London, England.;UCL, Dept Neurodegenerat Dis, UCL Inst Neurol, London, England..
    Blennow, Kaj
    Sahlgrens Univ Hosp, Clin Neurochem Lab, Mölndal, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Mölndal, Sweden..
    Chen, Christopher
    Natl Univ Singapore, Memory Aging & Cognit Ctr, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore.;Natl Univ Singapore, Memory Aging & Cognit Ctr, Yong Loo Lin Sch Med, Dept Psychol Med, Singapore, Singapore..
    Perry, George
    Univ Texas San Antonio, Dept Biol, San Antonio, TX USA.;Univ Texas San Antonio, Inst Neurosci, San Antonio, TX USA..
    Kim, Seung Hyun
    Hanyang Univ, Coll Med, Dept Neurol, Seoul, South Korea.;Hanyang Univ Hosp, Cell Therapy Ctr, Seoul, South Korea..
    Villemagne, Victor L.
    Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA.;Univ Melbourne, Dept Med, Melbourne, Vic, Australia..
    Aisen, Paul
    USC Alzheimers Therapeut Res Inst, San Diego, CA USA..
    Vendruscolo, Michele
    Univ Cambridge, Ctr Misfolding Dis, Dept Chem, Cambridge, England..
    Iwatsubo, Takeshi
    Univ Tokyo, Grad Sch Med, Dept Neuropathol, Tokyo, Japan..
    Masters, Colin L.
    Florey Inst, Dementia Res, Parkville, Vic, Australia.;Univ Melbourne, Parkville, Vic, Australia..
    Cho, Min
    Eisai Inc, Neurol Business Grp, Woodcliff Lake, NJ 07677 USA..
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. BioArct AB, Stockholm, Sweden..
    Cummings, Jeffrey L.
    Univ Nevada Las Vegas, Sch Integrated Hlth Sci, Dept Brain Hlth, Chambers Grundy Ctr Transformat Neurosci, Las Vegas, NV USA..
    Vergallo, Andrea
    Eisai Inc, Neurol Business Grp, Woodcliff Lake, NJ 07677 USA..
    The Amyloid-beta Pathway in Alzheimer's Disease2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 10, s. 5481-5503Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Breakthroughs in molecular medicine have positioned the amyloid-beta (A beta) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the A beta cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of A beta science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of A beta pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct A beta species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for A beta-targeting therapeutic strategies in development for the early treatment of AD.

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  • 16.
    Hjorth, Olof
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Frick, Andreas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Ekselius: Psykiatri.
    Gingnell, Malin
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Ekselius: Psykiatri.
    Hoppe, Johanna M.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Faria, Vanda
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Center for Pain and the Brain, Department of Anesthesiology Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School; Smell & Taste Clinic, Department of Otorhinolaryngology, TU Dresden.
    Hultberg, Sara
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Alaie, Iman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri.
    Månsson, Kristoffer N T
    Centre for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Wahlstedt, Kurt
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Jonasson, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Expression and co-expression of serotonin and dopamine transporters in social anxiety disorder: a multitracer positron emission tomography study2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 8, s. 3970-3979Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Serotonin and dopamine are putatively involved in the etiology and treatment of anxiety disorders, but positron emission tomography (PET) studies probing the two neurotransmitters in the same individuals are lacking. The aim of this multitracer PET study was to evaluate the regional expression and co-expression of the transporter proteins for serotonin (SERT) and dopamine (DAT) in patients with social anxiety disorder (SAD). Voxel-wise binding potentials (BPND) for SERT and DAT were determined in 27 patients with SAD and 43 age- and sex-matched healthy controls, using the radioligands [11C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) and [11C]PE2I (N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane). Results showed that, within transmitter systems, SAD patients exhibited higher SERT binding in the nucleus accumbens while DAT availability in the amygdala, hippocampus, and putamen correlated positively with symptom severity. At a more lenient statistical threshold, SERT and DAT BPND were also higher in other striatal and limbic regions in patients, and correlated with symptom severity, whereas no brain region showed higher binding in healthy controls. Moreover, SERT/DAT co-expression was significantly higher in SAD patients in the amygdala, nucleus accumbens, caudate, putamen, and posterior ventral thalamus, while lower co-expression was noted in the dorsomedial thalamus. Follow-up logistic regression analysis confirmed that SAD diagnosis was significantly predicted by the statistical interaction between SERT and DAT availability, in the amygdala, putamen, and dorsomedial thalamus. Thus, SAD was associated with mainly increased expression and co-expression of the transporters for serotonin and dopamine in fear and reward-related brain regions. Resultant monoamine dysregulation may underlie SAD symptomatology and constitute a target for treatment.

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    fulltext
  • 17.
    Hu, H.
    et al.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Haas, S. A.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Chelly, J.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Van Esch, H.
    Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium..
    Raynaud, M.
    INSERM, Imaging & Brain U930, Tours, France.;Univ Tours, Tours, France.;Ctr Hosp Reg Univ, Serv Genet, Tours, France..
    de Brouwer, A. P. M.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Weinert, S.
    Max Delbruck Centrum Mol Med, Berlin, Germany.;Leibniz Inst Mol Pharmacol, Berlin, Germany..
    Froyen, G.
    VIB Ctr Biol Dis, Human Genome Lab, Leuven, Belgium.;Katholieke Univ Leuven, Dept Human Genet, Human Genome Lab, Leuven, Belgium..
    Frints, S. G. M.
    Maastricht Univ, Med Ctr, AzM, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, GROW, Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands..
    Laumonnier, F.
    INSERM, Imaging & Brain U930, Tours, France.;Univ Tours, Tours, France..
    Zemojtel, T.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Love, M. I.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Richard, H.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Emde, A-K
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Bienek, M.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Jensen, C.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Hambrock, M.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Fischer, U.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Langnick, C.
    Max Delbruck Centrum Mol Med, Berlin, Germany..
    Feldkamp, M.
    Max Delbruck Centrum Mol Med, Berlin, Germany..
    Wissink-Lindhout, W.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Lebrun, N.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Castelnau, L.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Rucci, J.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Montjean, R.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Dorseuil, O.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Billuart, P.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Stuhlmann, T.
    Max Delbruck Centrum Mol Med, Berlin, Germany.;Leibniz Inst Mol Pharmacol, Berlin, Germany..
    Shaw, M.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia.;Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia..
    Corbett, M. A.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia.;Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia..
    Gardner, A.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia.;Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia..
    Willis-Owen, S.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia.;Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England..
    Tan, C.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia..
    Friend, K. L.
    Womens & Childrens Hosp, SA Pathol, Adelaide, SA, Australia..
    Belet, S.
    VIB Ctr Biol Dis, Human Genome Lab, Leuven, Belgium.;Katholieke Univ Leuven, Dept Human Genet, Human Genome Lab, Leuven, Belgium..
    van Roozendaal, K. E. P.
    Maastricht Univ, Med Ctr, AzM, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, GROW, Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands..
    Jimenez-Pocquet, M.
    Ctr Hosp Reg Univ, Serv Genet, Tours, France..
    Moizard, M-P
    INSERM, Imaging & Brain U930, Tours, France.;Univ Tours, Tours, France.;Ctr Hosp Reg Univ, Serv Genet, Tours, France..
    Ronce, N.
    INSERM, Imaging & Brain U930, Tours, France.;Univ Tours, Tours, France.;Ctr Hosp Reg Univ, Serv Genet, Tours, France..
    Sun, R.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    O'Keeffe, S.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Chenna, R.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Van Boemmel, A.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Goeke, J.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Hackett, A.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Field, M.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Christie, L.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Boyle, J.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Haan, E.
    Womens & Childrens Hosp, SA Pathol, Adelaide, SA, Australia..
    Nelson, J.
    King Edward Mem Hosp, Genet Serv Western Australia, Perth, WA, Australia..
    Turner, G.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Baynam, G.
    King Edward Mem Hosp, Genet Serv Western Australia, Perth, WA, Australia.;Univ Western Australia, Sch Paediat & Child Hlth, Perth, WA 6009, Australia.;Murdoch Univ, Inst Immunol & Infect Dis, Perth, WA, Australia.;Telethon Kids Inst, Perth, WA, Australia..
    Gillessen-Kaesbach, G.
    Univ Lubeck, Inst Humangenet, Lubeck, Germany..
    Mueller, U.
    Univ Giessen, Inst Humangenet, D-35390 Giessen, Germany.;Biol Ctr Human Genet, Frankfurt, Germany..
    Steinberger, D.
    Univ Giessen, Inst Humangenet, D-35390 Giessen, Germany.;Biol Ctr Human Genet, Frankfurt, Germany..
    Budny, B.
    Ponzan Univ Med Sci, Chair Dept Endocrinol Metab & Internal Dis, Poznan, Poland..
    Badura-Stronka, M.
    Ponzan Univ Med Sci, Chair Dept Med Genet, Poznan, Poland..
    Latos-Bielenska, A.
    Ponzan Univ Med Sci, Chair Dept Med Genet, Poznan, Poland..
    Ousager, L. B.
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark..
    Wieacker, P.
    Univ Klinikum Munster, Inst Humangenet, Munster, Germany..
    Criado, G. Rodriguez
    Hosp Virgen Rocio, Unidad Genet Clin, Seville, Spain..
    Bondeson, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Annerén, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Dufke, A.
    Inst Med Genet & Angew Genom, Tubingen, Germany..
    Cohen, M.
    Kinderzentrum Munchen, Munich, Germany..
    Van Maldergem, L.
    Univ Franche Comte, Ctr Genet Humaine, F-25030 Besancon, France..
    Vincent-Delorme, C.
    CHRU Lilles, Hop Jeanne Flandre, Serv Genet, Lille, France..
    Echenne, B.
    CHU Montpellier, Serve Neuropediat, Montpellier, France..
    Simon-Bouy, B.
    Ctr Hosp Versailles, Lab SESEP, Le Chesnay, France..
    Kleefstra, T.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Willemsen, M.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Fryns, J-P
    Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium..
    Devriendt, K.
    Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium..
    Ullmann, R.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Vingron, M.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Wrogemann, K.
    Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Wienker, T. F.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Tzschach, A.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    van Bokhoven, H.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Gecz, J.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia..
    Jentsch, T. J.
    Max Delbruck Centrum Mol Med, Berlin, Germany.;Leibniz Inst Mol Pharmacol, Berlin, Germany..
    Chen, W.
    Max Delbruck Centrum Mol Med, Berlin, Germany..
    Ropers, H-H
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Kalscheuer, V. M.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes2016Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, nr 1, s. 133-148Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

  • 18.
    Iyadurai, L.
    et al.
    Univ Oxford, Dept Psychiat, Oxford, England.
    Blackwell, S. E.
    MRC, Cognit & Brain Sci Unit, Cambridge, England;Ruhr Univ Bochum, Dept Clin Psychol & Psychotherapy, Bochum, Germany.
    Meiser-Stedman, R.
    Univ East Anglia, Dept Clin Psychol, Norwich, Norfolk, England.
    Watson, P. C.
    MRC, Cognit & Brain Sci Unit, Cambridge, England.
    Bonsall, M. B.
    Univ Oxford, Dept Zool, Oxford, England.
    Geddes, J. R.
    Univ Oxford, Dept Psychiat, Oxford, England;Oxford Hlth NHS Fdn Trust, Oxford, England.
    Nobre, A. C.
    Univ Oxford, Dept Psychiat, Oxford, England.
    Holmes, Emily A.
    Karolinska Inst, Div Psychol, Dept Clin Neurosci, SE-17177 Stockholm, Sweden.
    Preventing intrusive memories after trauma via a brief intervention involving Tetris computer game play in the emergency department: a proof-of-concept randomized controlled trial2018Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, nr 3, s. 674-682Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    After psychological trauma, recurrent intrusive visual memories may be distressing and disruptive. Preventive interventions post trauma are lacking. Here we test a behavioural intervention after real-life trauma derived from cognitive neuroscience. We hypothesized that intrusive memories would be significantly reduced in number by an intervention involving a computer game with high visuospatial demands (Tetris), via disrupting consolidation of sensory elements of trauma memory. The Tetris-based intervention (trauma memory reminder cue plus c. 20 min game play) vs attention-placebo control (written activity log for same duration) were both delivered in an emergency department within 6 h of a motor vehicle accident. The randomized controlled trial compared the impact on the number of intrusive trauma memories in the subsequent week (primary outcome). Results vindicated the efficacy of the Tetris-based intervention compared with the control condition: there were fewer intrusive memories overall, and time-series analyses showed that intrusion incidence declined more quickly. There were convergent findings on a measure of clinical post-trauma intrusion symptoms at 1 week, but not on other symptom clusters or at 1 month. Results of this proof-of-concept study suggest that a larger trial, powered to detect differences at 1 month, is warranted. Participants found the intervention easy, helpful and minimally distressing. By translating emerging neuroscientific insights and experimental research into the real world, we offer a promising new low-intensity psychiatric intervention that could prevent debilitating intrusive memories following trauma.

  • 19. Jacobs, M M
    et al.
    Okvist, A
    Horvath, Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Rättsmedicin.
    Keller, E
    Bannon, M J
    Morgello, S
    Hurd, Y L
    Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels2013Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 18, nr 11, s. 1205-1210Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine-glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine-glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single-nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the United States. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene-gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amygdala; the correlation was inversed in opiate abusers as compared with controls. Cumulatively, these results support the hypothesis that there may be significant, genetically influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers.

  • 20.
    Jia, Tianye
    et al.
    Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England.;Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Shanghai, Peoples R China.;Fudan Univ, MOE Key Lab Computat Neurosci & Brain Inspired In, Shanghai, Peoples R China..
    Chu, Congying
    Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England..
    Liu, Yun
    Fudan Univ, Zhongshan Hosp, Sch Basic Med Sci, Dept Biochem & Mol Biol,MOE Key Lab Metab & Mol M, Shanghai, Peoples R China..
    van Dongen, Jenny
    Vrije Univ Amsterdam, Dept Biol Psychol, Van der Boechorststr 1, NL-1081 BT Amsterdam, Netherlands..
    Papastergios, Evangelos
    Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England..
    Armstrong, Nicola J.
    Murdoch Univ, Math & Stat, Perth, WA, Australia..
    Bastin, Mark E.
    Univ Edinburgh MEB, Brain Res Imaging Ctr, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland.;Univ Edinburgh MEB, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland..
    Carrillo-Roa, Tania
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Kraepelinstr 2-10, D-80804 Munich, Germany..
    den Braber, Anouk
    Vrije Univ Amsterdam, Dept Biol Psychol, Van der Boechorststr 1, NL-1081 BT Amsterdam, Netherlands..
    Harris, Mathew
    Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Edinburgh Imaging, Edinburgh, Midlothian, Scotland..
    Jansen, Rick
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands..
    Liu, Jingyu
    Univ New Mexico, Dept Elect Engn, Albuquerque, NM 87131 USA..
    Luciano, Michelle
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland..
    Ori, Anil P. S.
    Univ Calif Los Angeles, UCLA Ctr Neurobehav Genet, Los Angeles, CA USA..
    Santianez, Roberto Roiz
    Univ Cantabria, Univ Hosp Marques de Valdecilla, Sch Med, Dept Psychiat, Santander, Spain.;Ctr Invest Biomed Red Salud Mental, Santander, Spain..
    Ruggeri, Barbara
    Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England..
    Sarkisyan, Daniil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Shin, Jean
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada..
    Sungeun, Kim
    Indiana Univ Sch Med, Ctr Neuroimaging, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA..
    Gutierrez, Diana Tordesillas
    Univ Cantabria, Univ Hosp Marques de Valdecilla, Sch Med, Dept Psychiat, Santander, Spain.;Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facil, Santander, Cantabria, Spain..
    van't Ent, Dennis
    Vrije Univ Amsterdam, Dept Biol Psychol, Van der Boechorststr 1, NL-1081 BT Amsterdam, Netherlands..
    Ames, David
    Natl Ageing Res Inst, Parkville, Vic, Australia.;Univ Melbourne, Acad Unit Psychiat Old Age, St Georges Hosp, Kew, Vic, Australia..
    Artiges, Eric
    Univ Paris 05, Inst Natl Sante & Rech Med, INSERM Unit 1000 Neuroimaging & Psychiat, Univ Paris Sud Paris Saclay, Orsay, France.;DIGITEO Labs, Gif Sur Yvette, France.;GH Nord Essonne Psychiat Dept 91G16, Orsay, France..
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Banaschewski, Tobias
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Med Fac Mannheim, Sq J5, D-68159 Mannheim, Germany..
    Bokde, Arun L. W.
    Trinity Coll Dublin, Sch Med, Discipline Psychiat, Dublin, Ireland.;Trinity Coll Dublin, Trinity Inst Neurosci, Dublin, Ireland..
    Brodaty, Henry
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia.;Univ New South Wales, Dementia Ctr Res Collaborat, Sch OfPsychiat, Sydney, NSW, Australia..
    Bromberg, Uli
    Univ Med Ctr Hamburg Eppendorf, House W34,3 OG,Martinistr 52, D-3 Hamburg, Germany..
    Brouwer, Rachel
    Univ Med Ctr Utrecht, Dept Psychiat, Utrecht, Netherlands.;Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Buchel, Christian
    Univ Med Ctr Hamburg Eppendorf, House W34,3 OG,Martinistr 52, D-3 Hamburg, Germany..
    Quinlan, Erin Burke
    Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England..
    Cahn, Wiepke
    Univ Med Ctr Utrecht, Dept Psychiat, Utrecht, Netherlands.;Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    de Zubicaray, Greig, I
    Queensland Univ Technol, Fac Hlth, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia..
    Ehrlich, Stefan
    Tech Univ Dresden, Div Psychol & Social Med & Dev Neurosci, Fac Med, Dresden, Germany..
    Ekstrom, Tomas J.
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Flor, Herta
    Heidelberg Univ, Med Fac Mannheim, CentralInst Mental Hlth, Dept Cognit & Clin Neurosci, Sq J5, Mannheim, Germany.;Univ Mannheim, Sch Social Sci, Dept Psychol, D-68131 Mannheim, Germany..
    Frohner, Juliane H.
    Tech Univ Dresden, Dept Psychiat, Dresden, Germany.;Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany..
    Frouin, Vincent
    Univ Paris Saclay, NeuroSpin, CEA, F-91191 Gif Sur Yvette, France..
    Garavan, Hugh
    Univ Vermont, Dept Psychiat, Burlington, VT 05405 USA..
    Gowland, Penny
    Univ Nottingham, Sir Peter Mansfield Imaging Ctr, Sch Phys & Astron, Univ Pk, Nottingham, England..
    Heinz, Andreas
    Charite Univ Med Berlin, Freie Univ Berlin, Humboldt Univ Berlin, Berlin, Germany.;Berlin Inst Hlth, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Charitepl 1, Berlin, Germany..
    Hoare, Jacqueline
    Univ Cape Town, Dept Psychiat, Cape Town, South Africa.;Univ Cape Town, Neurosci Inst, Cape Town, South Africa..
    Ittermann, Bernd
    Phys Tech Bundesanstalt PTB, Berlin, Germany..
    Jahanshad, Neda
    Univ Southern Calif, Keck Sch Med, Imaging Genet Ctr, Mark & Mary Stevens Neuroimaging & Informat Inst, Marina Del Rey, CA USA..
    Jiang, Jiyang
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia..
    Kwok, John B.
    Univ Sydney, Cent Clin Sch, Brain & Mind Ctr, Camperdown, NSW 2050, Australia.;Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia..
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld, Australia..
    Martinot, Jean-Luc
    Univ Paris 05, Inst Natl Sante & Rech Med, INSERM Unit 1000 Neuroimaging & Psychiat, Univ Paris Sud Paris Saclay, Orsay, France.;DIGITEO Labs, Gif Sur Yvette, France.;Cochin Hosp, Maison Solenn, Paris, France..
    Mather, Karen A.
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia.;Neurosci Res Australia, Sydney, NSW, Australia..
    McMahon, Katie L.
    Queensland Univ Technol, Sch Clin Sci, Herston Imaging Res Facil, Brisbane, Qld, Australia..
    McRae, Allan F.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Nees, Frauke
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Med Fac Mannheim, Sq J5, D-68159 Mannheim, Germany.;Heidelberg Univ, Med Fac Mannheim, CentralInst Mental Hlth, Dept Cognit & Clin Neurosci, Sq J5, Mannheim, Germany..
    Orfanos, Dimitri Papadopoulos
    Univ Paris Saclay, NeuroSpin, CEA, F-91191 Gif Sur Yvette, France..
    Paus, Tomas
    Univ Toronto, Bloorview Res Inst, Holland Bloorview Kids Rehabil Hosp, Toronto, ON M6A 2E1, Canada.;Univ Toronto, Dept Psychol, Toronto, ON M6A 2E1, Canada.;Univ Toronto, Dept Psychiat, Toronto, ON M6A 2E1, Canada..
    Poustka, Luise
    Univ Med Ctr Gottingen, Dept Child & Adolescent Psychiat & Psychotherapy, von Siebold Str 5, D-37075 Gottingen, Germany..
    Samann, Philipp G.
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Kraepelinstr 2-10, D-80804 Munich, Germany..
    Schofield, Peter R.
    Neurosci Res Australia, Sydney, NSW, Australia.;Univ New South Wales, Fac Med, Sydney, NSW, Australia..
    Smolka, Michael N.
    Tech Univ Dresden, Dept Psychiat, Dresden, Germany.;Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany..
    Stein, Dan J.
    Univ Cape Town, Dept Psychiat, Cape Town, South Africa.;Univ Cape Town, Neurosci Inst, Cape Town, South Africa.;SAMRC Unit Risk & Resilience Mental Disorders, Cape Town, South Africa..
    Strike, Lachlan T.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Teeuw, Jalmar
    Univ Calif Los Angeles, UCLA Ctr Neurobehav Genet, Los Angeles, CA USA.;Univ Med Ctr Utrecht, Dept Psychiat, Utrecht, Netherlands.;Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Thalamuthu, Anbupalam
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia.;Neurosci Res Australia, Sydney, NSW, Australia..
    Trollor, Julian
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia.;Univ New South Wales, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Sydney, NSW, Australia..
    Walter, Henrik
    Charite Univ Med Berlin, Freie Univ Berlin, Humboldt Univ Berlin, Berlin, Germany.;Berlin Inst Hlth, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Charitepl 1, Berlin, Germany..
    Wardlaw, Joanna M.
    Univ Edinburgh, Brain Res Imaging Ctr, Ctr Clin Brain Sci, Edinburgh Dementia Res Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, UK Dementia Res Inst, Edinburgh, Midlothian, Scotland..
    Wen, Wei
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia..
    Whelan, Robert
    Trinity Coll Dublin, Sch Psychol, Dublin, Ireland.;Trinity Coll Dublin, Global Brain Hlth Inst, Dublin, Ireland..
    Apostolova, Liana G.
    Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA..
    Binder, Elisabeth B.
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Kraepelinstr 2-10, D-80804 Munich, Germany..
    Boomsma, Dorret, I
    Vrije Univ Amsterdam, Dept Biol Psychol, Van der Boechorststr 1, NL-1081 BT Amsterdam, Netherlands..
    Calhoun, Vince
    Univ New Mexico, Dept Elect Engn, Albuquerque, NM 87131 USA.;Emory Univ, Triinst Ctr Translat Res Neuroimaging & Data Sci, Atlanta, GA 30303 USA..
    Crespo-Facorro, Benedicto
    Univ Cantabria, Univ Hosp Marques de Valdecilla, Sch Med, Dept Psychiat, Santander, Spain..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland..
    Pol, Hilleke Hulshoff
    Univ Med Ctr Utrecht, Dept Psychiat, Utrecht, Netherlands.;Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Ophoff, Roel A.
    Univ Med Ctr Utrecht, Dept Psychiat, Utrecht, Netherlands.;Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands.;Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA..
    Pausova, Zdenka
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada..
    Sachdev, Perminder S.
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia.;Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia..
    Saykin, Andrew
    Indiana Univ Sch Med, Radiol & Imaging Sci, Indianapolis, IN 46202 USA..
    Wright, Margaret J.
    QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld, Australia..
    Thompson, Paul M.
    Univ Southern Calif, Keck Sch Med, Imaging Genet Ctr, Mark & Mary Stevens Neuroimaging & Informat Inst, Marina Del Rey, CA USA..
    Schumann, Gunter
    Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England..
    Desrivieres, Sylvane
    Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England..
    Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 8, s. 3884-3895Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

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  • 21. Kuja-Halkola, Ralf
    et al.
    Lind Juto, Kristina
    Skoglund, Charlotte
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet; Stockholm Health Care Services, Stockholm County Council.
    Rück, Christian
    Mataix-Cols, David
    Pérez-Vigil, Ana
    Larsson, Johan
    Hellner, Clara
    Långström, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Petrovic, Predrag
    Lichtenstein, Paul
    Larsson, Henrik
    Do borderline personality disorder and attention-deficit/hyperactivity disorder co-aggregate in families?: A population-based study of 2 million Swedes2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 1, s. 341-349Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we included individuals born in Sweden 1979-2001, and identified their diagnoses during 1997-2013; in total, 2,113,902 individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient care. Individuals with an ADHD diagnosis had an adjusted (for birth year, sex, and birth order) odds ratio (aOR) of 19.4 (95% confidence interval [95% CI] = 18.6-20.4) of also having a BPD diagnosis, compared to individuals not diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD (monozygotic twins, aOR = 11.2, 95% CI = 3.0-42.2; full siblings, aOR = 2.8, 95% CI = 2.6-3.1; maternal half-siblings, aOR = 1.4, 95% CI = 1.2-1.7; paternal half-siblings, aOR = 1.5, 95% CI = 1.3-1.7). Cousins also had an increased risk. The strength of the association between ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of increased risks for BPD in individuals with ADHD and their relatives, and vice versa.

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  • 22.
    Kumar, Amit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi. Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Koistinen, Niina A.
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Malarte, Mona-Lisa
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Nennesmo, Inger
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ghetti, Bernardino
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
    Lemoine, Laetitia
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Nordberg, Agneta
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Astroglial tracer BU99008 detects multiple binding sites in Alzheimer’s disease brain2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 10, s. 5833-5847Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    With reactive astrogliosis being established as one of the hallmarks of Alzheimer’s disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.

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  • 23.
    Lalouni, Maria
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Fust, Jens
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Bjureberg, Johan
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Reg Stockholm, Stockholm Hlth Care Serv, Stockholm, Sweden.;Stanford Univ, Dept Psychol, Stanford, CA USA..
    Kastrati, Granit
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Fondberg, Robin
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Fransson, Peter
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Jayaram-Lindstrom, Nitya
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Reg Stockholm, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Kosek, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Klinisk smärtforskning. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Hellner, Clara
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.;Reg Stockholm, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Jensen, Karin B.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Augmented pain inhibition and higher integration of pain modulatory brain networks in women with self-injury behavior2022Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, nr 8, s. 3452-3459Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Individuals who engage in nonsuicidal self-injury (NSSI) have demonstrated insensitivity to pain compared with individuals without NSSI. Yet, the neural mechanisms behind this difference are unknown. The objective of the present study was to determine which aspects of the pain regulatory system that account for this decreased sensitivity to pain. In a case-control design, 81 women, aged 18-35 (mean [SD] age, 23.4 [3.9]), were included (41 with NSSI and 40 healthy controls). A quantitative sensory testing protocol, including heat pain thresholds, heat pain tolerance, pressure pain thresholds, conditioned pain modulation (assessing central down-regulation of pain), and temporal summation (assessing facilitation of pain signals) was used. Pain-evoked brain responses were assessed by means of fMRI scanning during thermal pain. NSSI participants showed a more effective central down-regulation of pain, compared to controls, assessed with conditioned pain modulation. The neural responses to painful stimulation revealed a stronger relation between nociceptive and pain modulatory brain regions in NSSI compared to controls. In line with previous studies, pressure and heat pain thresholds were higher in participants with NSSI, however, there were no correlations between pain outcomes and NSSI clinical characteristics. The augmented pain inhibition and higher involvement of pain modulatory brain networks in NSSI may represent a pain insensitive endophenotype associated with a greater risk for developing self-injurious behavior.

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  • 24. Lambert, J-C
    et al.
    Grenier-Boley, B.
    Harold, D.
    Zelenika, D.
    Chouraki, V.
    Kamatani, Y.
    Sleegers, K.
    Ikram, M. A.
    Hiltunen, M.
    Reitz, C.
    Mateo, I.
    Feulner, T.
    Bullido, M.
    Galimberti, D.
    Concari, L.
    Alvarez, V.
    Sims, R.
    Gerrish, A.
    Chapman, J.
    Deniz-Naranjo, C.
    Solfrizzi, V.
    Sorbi, S.
    Arosio, B.
    Spalletta, G.
    Siciliano, G.
    Epelbaum, J.
    Hannequin, D.
    Dartigues, J-F
    Tzourio, C.
    Berr, C.
    Schrijvers, E. M. C.
    Rogers, R.
    Tosto, G.
    Pasquier, F.
    Bettens, K.
    Van Cauwenberghe, C.
    Fratiglioni, L.
    Graff, C.
    Delepine, M.
    Ferri, R.
    Reynolds, C. A.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Prince, J. A.
    Chillotti, C.
    Pilotto, A.
    Seripa, D.
    Boland, A.
    Mancuso, M.
    Bossu, P.
    Annoni, G.
    Nacmias, B.
    Bosco, P.
    Panza, F.
    Sanchez-Garcia, F.
    Del Zompo, M.
    Coto, E.
    Owen, M.
    O'Donovan, M.
    Valdivieso, F.
    Caffara, P.
    Scarpini, E.
    Combarros, O.
    Buee, L.
    Campion, D.
    Soininen, H.
    Breteler, M.
    Riemenschneider, M.
    Van Broeckhoven, C.
    Alperovitch, A.
    Lathrop, M.
    Tregouet, D-A
    Williams, J.
    Amouyel, P.
    Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease2013Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 18, nr 4, s. 461-470Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 x 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and A beta plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma A beta 42/A beta 40 ratio (best signal, P=5.4 x 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

  • 25.
    Lemoine, Laetitia
    et al.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden..
    Gillberg, Per-Goran
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden..
    Bogdanovic, Nenad
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Aging Brain, Theme Aging, Stockholm, Sweden..
    Nennesmo, Inger
    Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden..
    Saint-Aubert, Laure
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.;Univ Toulouse, Toulouse NeuroImaging Ctr, ToNIC, INSERM,UPS, Toulouse, France.;Univ Hosp Toulouse, Nucl Med Dept, Toulouse, France..
    Viitanen, Matti
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Aging Brain, Theme Aging, Stockholm, Sweden.;Turku Univ, Turku City Hosp, Dept Geriatr, Turku, Finland..
    Graff, Caroline
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Unit Hereditary Dementia, Theme Aging, Stockholm, Sweden..
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nordberg, Agneta
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Aging Brain, Theme Aging, Stockholm, Sweden..
    Lack of fibrillar amyloid plaques but hypometabolism and astrogliosis in autosomal dominant variant AssPParc Alzheimer's disease2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 10, s. 5471-5471Artikel i tidskrift (Övrigt vetenskapligt)
  • 26.
    Lemoine, Laetitia
    et al.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden..
    Gillberg, Per-Goran
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden..
    Bogdanovic, Nenad
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Aging Brain, Theme Aging, Stockholm, Sweden..
    Nennesmo, Inger
    Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden..
    Saint-Aubertlfis, Laure
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.;Univ Toulouse, Toulouse NeuroImaging Ctr, UPS, INSERM,ToNIC, Toulouse, France.;Univ Hosp Toulouse, Nucl Med Dept, Toulouse, France..
    Viitanen, Matti
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Aging Brain, Theme Aging, Stockholm, Sweden.;Turku Univ, Turku City Hosp, Dept Geriatr, Turku, Finland..
    Graff, Caroline
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Unit Hereditary Dementia, Theme Aging, Stockholm, Sweden..
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nordberg, Agneta
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Aging Brain, Theme Aging, Stockholm, Sweden..
    Amyloid, tau, and astrocyte pathology in autosomal-dominant Alzheimer's disease variants: A beta PParc and PSEN1DE92021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 10, s. 5609-5619Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using(11)C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer's disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with(3)H-PiB,H-3-MK6240-H-3-THK5117, and(3)H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in twoA beta PParcmutation carriers, onePSEN1 Delta E9mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding inA beta PParc. A high binding was observed inPSEN1 Delta E9and in sAD tissues but with different binding patterns. Comparable(3)H-THK5117 and(3)H-deprenyl brain homogenate binding was observed forA beta PParc,PSEN1 Delta E9, and sAD, respectively. Some differences were observed between(3)H-MK6240 and(3)H-THK5117 in ADAD. A positive correlation between(3)H-deprenyl and(3)H-THK5117 binding was observed inA beta PParc, while no such correlation was found inPSEN1 Delta E9and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in theA beta PParccases, high regional tau and astrocyte binding was observed. The lack of correlation between(3)H-deprenyl and(3)H-THK5117 binding inPSEN1 Delta E9and sAD in contrast of the positive correlation observed in theA beta PParccases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.

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  • 27. Lindblad, K
    et al.
    Nylander, PO
    Zander, C
    Yuan, QP
    Ståhle, L
    Engström, C
    Balciuniene, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Breschel, T
    McInnis, M
    Ross, CA
    Adolfsson, R
    Schalling, M
    Two commonly expanded CAG/CTG repeat loci: involvement in affectivedisorders?1998Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 3, nr 5, s. 405-410Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An association between bipolar affective disorder and CAG/CTG trinucleotide repeat expansions (TRE) has previously been detected using the repeat expansion detection (RED) method. Here we report that 89% of RED products (CAG/CTG repeats) > 120 nt (n = 202) detected in affective disorder patients as well as unaffected family members and controls correlate with expansions at two repeat loci, ERDA1 on chromosome 17q21.3 and CTG18.1 on 18q21.1. In a set of patients and controls in which we had previously found a significant difference in RED size distribution, the frequency of expansions at the CTG18.1 locus was 13% in bipolar patients (n = 60) and 5% in controls (n = 114) (P < 0.07) with a significantly different size distribution (P < 0.03). A second set of patients were ascertained from 14 affective disorder families showing anticipation. Twelve of the families had members with RED products > 120 nt. The RED product distribution was significantly different (P < 0.0007) between affected (n = 53) and unaffected (n = 123) offspring. Using PCR, a higher frequency (P < 0.04) of CTG18.1 expansions as well as a different (P < 0.02) repeat size distribution was seen between affected and unaffected offspring. In addition, a negative correlation between RED product size and the age-of-onset could be seen in affected offspring (rs = -0.3, P = 0.05, n = 43). This effect was due to an earlier onset in individuals with long CTG18.1 expansions. No difference in ERDA1 expansion frequency was seen either between bipolar patients (35%, n = 60) and matched controls (29%, n = 114), or between affected and unaffected offspring in the families. We conclude that expanded alleles at the CTG18.1 locus confers an odds ratio of 2.6-2.8 and may thus act as a vulnerability factor for affective disorder, while the ERDA1 locus seems unrelated to disease.

  • 28. Lips, E. S.
    et al.
    Cornelisse, L. N.
    Toonen, R. F.
    Min, J. L.
    Hultman, C. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Ulleråker, Akademiska sjukhuset.
    Holmans, P. A.
    O'Donovan, M. C.
    Purcell, S. M.
    Smit, A. B.
    Verhage, M.
    Sullivan, P. F.
    Visscher, P. M.
    Posthuma, D.
    Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia2012Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 17, nr 10, s. 996-1006Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of similar to 1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P = 7.6 x 10(-11)) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P < 0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P = 2.0 x 10(-4)), excitability (P = 9.0 x 10(-4)) and cell adhesion and trans-synaptic signaling (P = 2.4 x 10(-3)). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia. Molecular Psychiatry (2012) 17, 996-1006; doi:10.1038/mp.2011.117; published online 20 September 2011

  • 29. Liu, C
    et al.
    Marioni, R E
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pfeiffer, L
    Tsai, P-C
    Reynolds, L M
    Just, A C
    Duan, Q
    Boer, C G
    Tanaka, T
    Elks, C E
    Aslibekyan, S
    Brody, J A
    Kühnel, B
    Herder, C
    Almli, L M
    Zhi, D
    Wang, Y
    Huan, T
    Yao, C
    Mendelson, M M
    Joehanes, R
    Liang, L
    Love, S-A
    Guan, W
    Shah, S
    McRae, A F
    Kretschmer, A
    Prokisch, H
    Strauch, K
    Peters, A
    Visscher, P M
    Wray, N R
    Guo, X
    Wiggins, K L
    Smith, A K
    Binder, E B
    Ressler, K J
    Irvin, M R
    Absher, D M
    Hernandez, D
    Ferrucci, L
    Bandinelli, S
    Lohman, K
    Ding, J
    Trevisi, L
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stolk, L
    Uitterlinden, A G
    Yet, I
    Castillo-Fernandez, J E
    Spector, T D
    Schwartz, J D
    Vokonas, P
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Li, Y
    Fornage, M
    Arnett, D K
    Wareham, N J
    Sotoodehnia, N
    Ong, K K
    van Meurs, J B J
    Conneely, K N
    Baccarelli, A A
    Deary, I J
    Bell, J T
    North, K E
    Liu, Y
    Waldenberger, M
    London, S J
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
    Levy, D
    A DNA methylation biomarker of alcohol consumption.2018Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, s. 422-433Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

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  • 30.
    Loryan, Irena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Melander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Svensson, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Payan, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    König, F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jansson, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy2016Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, nr 11, s. 1527-1536Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The current study provides a novel in-depth assessment of the extent of antipsychotic drugs transport across the blood-brain barrier (BBB) into various brain regions, as well as across the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). This is combined with an estimation of cellular barrier transport and a systematic evaluation of nonspecific brain tissue binding. The study is based on the new Combinatory Mapping Approach (CMA), here further developed for the assessment of unbound drug neuropharmacokinetics in regions of interest (ROI), referred as CMA-ROI. We show that differences exist between regions in both BBB transport and in brain tissue binding. The most dramatic spatial differences in BBB transport were found for the P-glycoprotein substrates risperidone (5.4-fold) and paliperidone (4-fold). A higher level of transporter-mediated protection was observed in the cerebellum compared with other brain regions with a more pronounced efflux for quetiapine, risperidone and paliperidone. The highest BBB penetration was documented in the frontal cortex, striatum and hippocampus (haloperidol, olanzapine), indicating potential influx mechanisms. BSCB transport was in general characterized by more efficient efflux compared with the brain regions. Regional tissue binding was significantly different for haloperidol, clozapine, risperidone and quetiapine (maximally 1.9-fold). Spatial differences in local unbound concentrations were found to significantly influence cortical 5-HT2A receptor occupancy for risperidone and olanzapine. In conclusion, the observed regional differences in BBB penetration may potentially be important factors contributing to variations in therapeutic effect and side effect profiles among antipsychotic drugs.

  • 31.
    Luptáková, Dominika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Vallianatou, Theodosia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nilsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Shariatgorji, Reza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Loryan, Irena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Neuropharmacokinetic visualization of regional and subregional unbound antipsychotic drug transport across the blood-brain barrier.2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, s. 7732-7745Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Comprehensive determination of the extent of drug transport across the region-specific blood-brain barrier (BBB) is a major challenge in preclinical studies. Multiple approaches are needed to determine the regional free (unbound) drug concentration at which a drug engages with its therapeutic target. We present an approach that merges in vivo and in vitro neuropharmacokinetic investigations with mass spectrometry imaging to quantify and visualize both the extent of unbound drug BBB transport and the post-BBB cerebral distribution of drugs at regional and subregional levels. Direct imaging of the antipsychotic drugs risperidone, clozapine, and olanzapine using this approach enabled differentiation of regional and subregional BBB transport characteristics at 20-µm resolution in small brain regions, which could not be achieved by other means. Our approach allows investigation of heterogeneity in BBB transport and presents new possibilities for molecular psychiatrists by facilitating interpretation of regional target-site exposure results and decision-making.

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  • 32.
    Meng, Weida
    et al.
    Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, MOE Key Lab Metab & Mol Med, Shanghai, Peoples R China.;Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China.;Fudan Univ, Inst Brain Sci, Frontiers Ctr Brain Sci, State Key Lab Med Neurobiol, Shanghai, Peoples R China.;Fudan Univ, Inst Brain Sci, Frontiers Ctr Brain Sci, MOE, Shanghai, Peoples R China..
    Sjoholm, Louise K.
    Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden..
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Tay, Nicole
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, Ctr Populat Neurosci & Stratified Med PONS, London, England..
    Zhang, Dandan
    Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, MOE Key Lab Metab & Mol Med, Shanghai, Peoples R China.;Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China.;Fudan Univ, Inst Brain Sci, Frontiers Ctr Brain Sci, State Key Lab Med Neurobiol, Shanghai, Peoples R China.;Fudan Univ, Inst Brain Sci, Frontiers Ctr Brain Sci, MOE, Shanghai, Peoples R China..
    Sarkisyan, Daniil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Geske, Jennifer R.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Ing, Alex
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, Ctr Populat Neurosci & Stratified Med PONS, London, England..
    Qiu, Wenqing
    Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, MOE Key Lab Metab & Mol Med, Shanghai, Peoples R China.;Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China.;Fudan Univ, Inst Brain Sci, Frontiers Ctr Brain Sci, State Key Lab Med Neurobiol, Shanghai, Peoples R China.;Fudan Univ, Inst Brain Sci, Frontiers Ctr Brain Sci, MOE, Shanghai, Peoples R China..
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Almamoun, Radwa
    Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden..
    Frieling, Helge
    Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany..
    Bleich, Stefan
    Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany..
    Cui, Donghong
    Shanghai Jiao Tong Univ, Sch Med, Shanghai Mental Hlth Ctr, Shanghai Key Lab Psychot Disorders, Shanghai, Peoples R China..
    Biernacka, Joanna M.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Mayfield, R. Dayne
    Univ Texas Austin, Waggoner Ctr Alcohol & Addict Res, Austin, TX 78712 USA..
    Dang, Yongjun
    Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, MOE Key Lab Metab & Mol Med, Shanghai, Peoples R China.;Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China..
    Karpyak, Victor M.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Schumann, Gunter
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, Ctr Populat Neurosci & Stratified Med PONS, London, England..
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ekstrom, Tomas J.
    Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden..
    Ruegg, Joelle
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Liu, Yun
    Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, MOE Key Lab Metab & Mol Med, Shanghai, Peoples R China.;Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China.;Fudan Univ, Inst Brain Sci, Frontiers Ctr Brain Sci, State Key Lab Med Neurobiol, Shanghai, Peoples R China.;Fudan Univ, Inst Brain Sci, Frontiers Ctr Brain Sci, MOE, Shanghai, Peoples R China..
    Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 8, s. 4367-4382Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.

  • 33. Mätlik, Kärt
    et al.
    Garton, Daniel R
    Montaño-Rodríguez, Ana R
    Olfat, Soophie
    Eren, Feride
    Casserly, Laoise
    Damdimopoulos, Anastasios
    Panhelainen, Anne
    Porokuokka, L Lauriina
    Kopra, Jaakko J
    Turconi, Giorgio
    Schweizer, Nadine
    Bereczki, Erika
    Piehl, Fredrik
    Engberg, Göran
    Cervenka, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Psykiatri.
    Piepponen, T Petteri
    Zhang, Fu-Ping
    Sipilä, Petra
    Jakobsson, Johan
    Sellgren, Carl M
    Erhardt, Sophie
    Andressoo, Jaan-Olle
    Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia.2022Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2-3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.

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  • 34. Ng, M Y M
    et al.
    Levinson, D F
    Faraone, S V
    Suarez, B K
    DeLisi, L E
    Arinami, T
    Riley, B
    Paunio, T
    Pulver, A E
    Irmansyah,
    Holmans, P A
    Escamilla, M
    Wildenauer, D B
    Williams, N M
    Laurent, C
    Mowry, B J
    Brzustowicz, L M
    Maziade, M
    Sklar, P
    Garver, D L
    Abecasis, G R
    Lerer, B
    Fallin, M D
    Gurling, H M D
    Gejman, P V
    Lindholm, E
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Zoologisk utvecklingsbiologi.
    Moises, H W
    Byerley, W
    Wijsman, E M
    Forabosco, P
    Tsuang, M T
    Hwu, H-G
    Okazaki, Y
    Kendler, K S
    Wormley, B
    Fanous, A
    Walsh, D
    O'Neill, F A
    Peltonen, L
    Nestadt, G
    Lasseter, V K
    Liang, K Y
    Papadimitriou, G M
    Dikeos, D G
    Schwab, S G
    Owen, M J
    O'Donovan, M C
    Norton, N
    Hare, E
    Raventos, H
    Nicolini, H
    Albus, M
    Maier, W
    Nimgaonkar, V L
    Terenius, L
    Mallet, J
    Jay, M
    Godard, S
    Nertney, D
    Alexander, M
    Crowe, R R
    Silverman, J M
    Bassett, A S
    Roy, M-A
    Mérette, C
    Pato, C N
    Pato, M T
    Roos, J Louw
    Kohn, Y
    Amann-Zalcenstein, D
    Kalsi, G
    McQuillin, A
    Curtis, D
    Brynjolfson, J
    Sigmundsson, T
    Petursson, H
    Sanders, A R
    Duan, J
    Jazin, E
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Zoologisk utvecklingsbiologi.
    Myles-Worsley, M
    Karayiorgou, M
    Lewis, C M
    Meta-analysis of 32 genome-wide linkage studies of schizophrenia2009Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, nr 8, s. 774-785Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

  • 35.
    Orhan, F
    et al.
    Karolinska Inst, Stockholm, Sweden.
    Fatouros-Bergman, H
    Karolinska Inst, Stockholm, Sweden.
    Goiny, M
    Karolinska Inst, Stockholm, Sweden.
    Malmqvist, A
    Karolinska Inst, Stockholm, Sweden.
    Piehl, F
    Karolinska Inst, Stockholm, Sweden.
    Cervenka, Simon
    Karolinska Inst, Stockholm, Sweden.
    Collste, K
    Karolinska Inst, Stockholm, Sweden.
    Victorsson, P
    Karolinska Inst, Stockholm, Sweden.
    Sellgren, C M
    Karolinska Inst, Stockholm, Sweden; Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA.
    Flyckt, L
    Karolinska Inst, Stockholm, Sweden.
    Erhardt, S
    Karolinska Inst, Stockholm, Sweden.
    Engberg, G
    Karolinska Inst, Stockholm, Sweden.
    CSF GABA is reduced in first-episode psychosis and associates to symptom severity2018Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, nr 5, s. 1244-1250Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

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  • 36. Plavén-Sigray, Pontus
    et al.
    Ikonen Victorsson, Pauliina
    Santillo, Alexander
    Matheson, Granville J
    Lee, Maria
    Collste, Karin
    Fatouros-Bergman, Helena
    Sellgren, Carl M
    Erhardt, Sophie
    Agartz, Ingrid
    Halldin, Christer
    Farde, Lars
    Cervenka, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Cervenka: Psykiatri.
    Thalamic dopamine D2-receptor availability in schizophrenia: a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis.2022Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, nr 2, s. 1233-1240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [11C]FLB457. The main outcome was D2-R binding potential (BPND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen's dz = -0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BPND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen's dz = -0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen's d = -0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.

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  • 37.
    Ramineni, Varsha
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Millroth, Philip
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Iyadurai, Lalitha
    Jaki, Thomas
    Kingslake, Jonathan
    Highfield, Julie
    Summers, Charlotte
    Bonsall, Michael B.
    Holmes, Emily A.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Treating intrusive memories after trauma in healthcare workers: a Bayesian adaptive randomised trial developing an imagery-competing task intervention2023Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, nr 7, s. 2985-2994Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intensive care unit (ICU) staff continue to face recurrent work-related traumatic events throughout the COVID-19 pandemic. Intrusive memories (IMs) of such traumatic events comprise sensory image-based memories. Harnessing research on preventing IMs with a novel behavioural intervention on the day of trauma, here we take critical next steps in developing this approach as a treatment for ICU staff who are already experiencing IMs days, weeks, or months post-trauma. To address the urgent need to develop novel mental health interventions, we used Bayesian statistical approaches to optimise a brief imagery-competing task intervention to reduce the number of IMs. We evaluated a digitised version of the intervention for remote, scalable delivery. We conducted a two-arm, parallel-group, randomised, adaptive Bayesian optimisation trial. Eligible participants worked clinically in a UK NHS ICU during the pandemic, experienced at least one work-related traumatic event, and at least three IMs in the week prior to recruitment. Participants were randomised to receive immediate or delayed (after 4 weeks) access to the intervention. Primary outcome was the number of IMs of trauma during week 4, controlling for baseline week. Analyses were conducted on an intention-to-treat basis as a between-group comparison. Prior to final analysis, sequential Bayesian analyses were conducted (n = 20, 23, 29, 37, 41, 45) to inform early stopping of the trial prior to the planned maximum recruitment (n = 150). Final analysis (n = 75) showed strong evidence for a positive treatment effect (Bayes factor, BF = 1.25 × 106): the immediate arm reported fewer IMs (median = 1, IQR = 0–3) than the delayed arm (median = 10, IQR = 6–16.5). With further digital enhancements, the intervention (n = 28) also showed a positive treatment effect (BF = 7.31). Sequential Bayesian analyses provided evidence for reducing IMs of work-related trauma for healthcare workers. This methodology also allowed us to rule out negative effects early, reduced the planned maximum sample size, and allowed evaluation of enhancements. Trial Registration NCT04992390 (www.clinicaltrials.gov).

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  • 38.
    Reinius, Björn
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Zoologisk utvecklingsbiologi.
    Jazin, Elena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Zoologisk utvecklingsbiologi.
    mRNA expression of Y-linked transcripts in 12 regions of the prenatal human male brain (Featured Image)2009Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, nr 11, s. 987-Artikel i tidskrift (Refereegranskat)
  • 39.
    Reinius, Björn
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Zoologisk utvecklingsbiologi.
    Jazin, Elena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Zoologisk utvecklingsbiologi.
    Prenatal sex differences in the human brain2009Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, nr 11, s. 988-989Artikel i tidskrift (Refereegranskat)
  • 40. Sellgren, Carl M
    et al.
    Imbeault, Sophie
    Larsson, Markus K
    Oliveros, Alfredo
    Nilsson, Ida A K
    Codeluppi, Simone
    Orhan, Funda
    Bhat, Maria
    Tufvesson-Alm, Maximilian
    Gracias, Jessica
    Kegel, Magdalena E
    Zheng, Yiran
    Faka, Anthi
    Svedberg, Marie
    Powell, Susan B
    Caldwell, Sorana
    Kamenski, Mary E
    Vawter, Marquis P
    Schullman, Anton
    Goiny, Michel
    Svensson, Camilla I
    Hökfelt, Tomas
    Schalling, Martin
    Schwieler, Lilly
    Cervenka, Simon
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm & Stockholm Health Care Services, Region Stockholm, Sweden.
    Choi, Doo-Sup
    Landén, Mikael
    Engberg, Göran
    Erhardt, Sophie
    GRK3 deficiency elicits brain immune activation and psychosis2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 11, s. 6820-6832Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3-/- mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3-/- mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.

  • 41. Shahsavani, M
    et al.
    Pronk, R J
    Falk, R
    Lam, M
    Moslem, M
    Linker, S B
    Salma, J
    Day, K
    Schuster, Jens
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Anderlid, B-M
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gage, F H
    Falk, A
    An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis2018Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, nr 7, s. 1674-1684Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.Molecular Psychiatry advance online publication, 19 September 2017; doi:10.1038/mp.2017.175.

  • 42. Skoglund, Charlotte
    et al.
    Tiger, Annika
    Rück, Christian
    Petrovic, Predrag
    Asherson, Philip
    Hellner, Clara
    Mataix-Cols, David
    Kuja-Halkola, Ralf
    Familial risk and heritability of diagnosed borderline personality disorder: a register study of the Swedish population2021Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, nr 3, s. 999-1008Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Family and twin studies of Borderline Personality Disorder (BPD) have found familial aggregation and genetic propensity for BPD, but estimates vary widely. Large-scale family studies of clinically diagnosed BPD are lacking. Therefore, we performed a total-population study estimating the familial aggregation and heritability of clinically diagnosed BPD. We followed 1,851,755 individuals born 1973-1993 in linked Swedish national registries. BPD-diagnosis was ascertained between 1997 and 2013, 11,665 received a BPD-diagnosis. We identified relatives and estimated sex and birth year adjusted hazard ratios, i.e., the rate of BPD-diagnoses in relatives to individuals with BPD-diagnosis compared to individuals with unaffected relatives, and used structural equation modeling to estimate heritability. The familial association decreased along with genetic relatedness. The hazard ratio was 11.5 (95% confidence interval (CI) = 1.6-83.8) for monozygotic twins; 7.4 (95% CI = 1.0-55.3) for dizygotic twins; 4.7 (95% CI = 3.9-5.6) for full siblings; 2.1 (95% CI = 1.5-3.0) for maternal half-siblings; 1.3 (95% CI = 0.9-2.1) for paternal half-siblings; 1.7 (95% CI = 1.4-2.0) for cousins whose parents were full siblings; 1.1 (95% CI = 0.7-1.8) for cousins whose parents were maternal half-siblings; and 1.9 (95% CI = 1.2-2.9) for cousins whose parents were paternal half-siblings. Heritability was estimated at 46% (95% CI = 39-53), and the remaining variance was explained by individually unique environmental factors. Our findings pave the way for further research into specific genetic variants, unique environmental factors implicated, and their interplay in risk for BPD.

  • 43. Tingsborg, S
    et al.
    Ziólkowska, M
    Zetterström, M
    Hasanvan, H
    Bartfai, T
    Regulation of ICE activity and ICE isoforms by LPS.1997Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 2, nr 2, s. 122-4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interleukin 1 beta (IL-1 beta) is a highly inducible proinflammatory cytokine. It is processed to its mature, secreted 17-kDa form by a cysteine endoprotease; the interleukin 1 beta converting enzyme (ICE). Regulation of IL-1 beta levels can be achieved both at transcriptional and translational level and in particular at the posttranslational, ICE catalysed, level. Thus, we examined ICE activity in rats under conditions of systemic stimulation by intraperitoneal (i.p.) injections of lipopolysaccharide (LPS) from E. coli, which are known to dramatically alter IL-1 beta mRNA and protein levels. ICE mRNA levels and endoprotease activity have also been found to be differentially regulated in the rat adrenal gland and rat brain after i.p. injections of LPS. An induction in ICE mRNA levels could be seen in the adrenal gland, the pituitary and in the hypothalamus after LPS treatment as measured by reverse transcription-polymerase chain reaction (RT-PCR), whereas the ICE endoprotease activity was increased in the pituitary and decreased in the hippocampus and in the adrenal gland. The discrepancy between increased mRNA level for ICE and decreased enzyme activity in the adrenals might be explained by the induction of ICE isoforms, some of which might be inhibitory for the enzyme activity and induced by LPS, yielding as a net effect a suppression of ICE activity.

  • 44.
    Wen, Jia
    et al.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Trost, Brett
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada.;Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada..
    Engchuan, Worrawat
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada.;Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada..
    Halvorsen, Matthew
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Pallotto, Linda M.
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada..
    Mitina, Aleksandra
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada..
    Ancalade, NaEshia
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Farrell, Martilias
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Backstrom, Ian
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada..
    Guo, Keyi
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada..
    Pellecchia, Giovanna
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada.;Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada..
    Thiruvahindrapuram, Bhooma
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada.;Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada..
    Giusti-Rodriguez, Paola
    Univ Florida, Dept Psychiat, Coll Med, Gainesville, FL 32610 USA..
    Rosen, Jonathan David
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Li, Yun
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA..
    Won, Hyejung
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden..
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bassett, Anne S.
    Ctr Addict & Mental Hlth, Clin Genet Res Program, Toronto, ON M6J 1H4, Canada.;Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON M6J 1H4, Canada.;Univ Hlth Network, Dalglish Family Clin Adults Delet Syndrome 22q 22, Toronto Gen Hosp, Toronto, ON M5G 2C4, Canada.;Univ Hlth Network, Toronto Gen Hosp, Res Inst, Toronto, ON M5G 2C4, Canada.;Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada..
    Hultman, Christina M.
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden..
    Sullivan, Patrick F.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.;Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA..
    Yuen, Ryan K. C.
    Hosp Sick Children, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada..
    Szatkiewicz, Jin P.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA..
    Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia2023Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, nr 1, s. 475-482Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.

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