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  • 1.
    Backman, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Strandkvist, Viktor
    Department of Health and Technology, Luleå University of Technology, Luleå, Sweden.
    Sawalha, Sami
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Nilsson, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Eriksson Ström, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hedman, Linnea
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Stridsman, Caroline
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lung function trajectories and associated mortality among adults with and without airway obstruction2023In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 208, no 10, p. 1063-1074Article in journal (Refereed)
    Abstract [en]

    Rationale: Spirometry is essential for diagnosis and assessment of prognosis in COPD.

    Objectives: To identify FEV1 trajectories and their determinants, based on annual spirometry measurements among individuals with and without airway obstruction. Furthermore, to assess mortality in relation to trajectories.

    Methods: In 2002-04, individuals with airway obstruction (AO) (FEV1/VC<0.70, n=993) and age- and sex-matched non-obstructive (NO) referents were recruited from population-based cohorts. Annual spirometries until 2014 were utilized in joint-survival Latent Class Mixed Models to identify lung function trajectories. Mortality data were collected during 15 years of follow-up.

    Results: Three trajectories were identified among the AO-cases and two among the NO referents. Trajectory membership was driven by baseline FEV1%predicted (%pred) in both groups and additionaly, pack-years in AO and current smoking in NO. Longitudinal FEV1%pred level depended on baseline FEV1%pred, pack-years and obesity. The trajectories were distributed: 79.6% T1AO FEV1-high with normal decline, 12.8% T2AO FEV1-high with rapid decline, and 7.7% T3AO FEV1-low with normal decline (mean 27, 72 and 26 mL/year) among AO-individuals, and 96.7% T1NO FEV1-high with normal decline and 3.3% T2NO FEV1-high with rapid decline (mean 34 and 173 mL/year) among referents. Hazard for death was increased for T2AO (HR1.56) and T3AO (HR3.45) vs. T1AO, and for T2NO (HR2.99) vs. T1NO.

    Conclusions: Three different FEV1 trajectories were identified among those with airway obstruction and two among the referents, with different outcomes in terms of FEV1-decline and mortality. The FEV1 trajectories among airway obstructive and the relationship between low FVC and trajectory outcome are of particular clinical interest.

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  • 2.
    Berglin, Ewa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Esberg, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Dahlqvist, J.
    Sjowall, J.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Mohammad, A. J.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Protein profiling in individuals before onset of anca-associated vasculitis2020In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 79, p. 372-372Article in journal (Other academic)
  • 3.
    Boman, Antonia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Hansson, Monica
    Mathsson-Alm, Linda
    Rönnelid, Johan
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Holmdahl, Rikard
    Skriner, Karl
    Serre, Guy
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study2019In: RMD Open, E-ISSN 2056-5933, Vol. 5, no 2, article id e000946Article in journal (Refereed)
    Abstract [en]

    Introduction: Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort.

    Methods: The ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment.

    Results: Frequency of ACPA reactivities varied between 13.3% and 63.1%. Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%. Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were significantly associated with number of ACPA reactivities. The ACPA reactivities modified differently the development of DAS28 over 24 months (identified using trajectories). Anti-Filaggrin307-324, anti-hnRNP (Peptide)-Z1 and anti-F4-CIT-R antibodies anticipated lower DAS28 values (p<0.01–0.05), while positivity for anti-Fibrinogen(Fib)β62-78(74), and anti-Fibα563-583 predicted higher DAS28 (p<0.01 both). Interaction between anti-Fibß36-52, anti-Pept-5 and anti-Bla-26 antibodies, respectively, and DAS28 during 24 months decreased significantly the DAS28 values (p<0.01–0.05). Corticosteroids and biologicals were related to DAS28-area under the curve and Larsen score 24 months. Anti-vimentin2-17 antibodies remained significantly associated with Larsen score at baseline and 24 months, respectively, and radiological progression, besides biologicals at 24 months adjusted for sex and age.

    Conclusions: Several ACPA reactivities modified significantly the DAS28 development during the first 24 months and were significantly associated with Larsen score at baseline, 24 months and radiological progression.

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  • 4.
    Bondesson, Lennart
    et al.
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Traat, Imbi
    Institute of Mathematical Statistics , University of Tartu , Estonia.
    Lundquist, Anders
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Pareto sampling versus Sampford and Conditional Poisson sampling2006In: Scandinavian Journal of Statistics, ISSN 0303-6898, E-ISSN 1467-9469, Vol. 33, no 4, p. 699-720Article in journal (Refereed)
    Abstract [en]

    Pareto sampling was introduced by Rosén in the late 1990s. It is a simple method to get a fixed size πps sample though with inclusion probabilities only approximately as desired. Sampford sampling, introduced by Sampford in 1967, gives the desired inclusion probabilities but it may take time to generate a sample. Using probability functions and Laplace approximations, we show that from a probabilistic point of view these two designs are very close to each other and asymptotically identical. A Sampford sample can rapidly be generated in all situations by letting a Pareto sample pass an acceptance–rejection filter. A new very efficient method to generate conditional Poisson (CP) samples appears as a byproduct. Further, it is shown how the inclusion probabilities of all orders for the Pareto design can be calculated from those of the CP design. A new explicit very accurate approximation of the second-order inclusion probabilities, valid for several designs, is presented and applied to get single sum type variance estimates of the Horvitz–Thompson estimator.

  • 5.
    Boraxbekk, Carl-Johan
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nilsson, Lars-Göran
    Aging Research Center, Karolinska Institutet.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Free Recall Episodic Memory Performance Predicts Dementia 10 Years Prior to Clinical Diagnosis: Findings from the Betula Longitudinal Study2015In: Dementia and Geriatric Cognitive Disorders Extra, E-ISSN 1664-5464, Vol. 5, no 2, p. 191-202Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Early dementia diagnosis is a considerable challenge. The present study examined the predictive value of cognitive performance for a future clinical diagnosis of late-onset Alzheimer's disease or vascular dementia in a random population sample. Methods: Cognitive performance was retrospectively compared between three groups of participants from the Betula longitudinal cohort. Group 1 developed dementia 11-22 years after baseline testing (n = 111) and group 2 after 1-10 years (n = 280); group 3 showed no deterioration towards dementia during the study period (n = 2,855). Multinomial logistic regression analysis was used to investigate the predictive value of tests reflecting episodic memory performance, semantic memory performance, visuospatial ability, and prospective memory performance. Results: Age-and education-corrected performance on two free recall episodic memory tests significantly predicted dementia 10 years prior to clinical diagnosis. Free recall performance also predicted dementia 11-22 years prior to diagnosis when controlling for education, but not when age was added to the model. Conclusion: The present results support the suggestion that two free recall-based tests of episodic memory function may be useful for detecting individuals at risk of developing dementia 10 years prior to clinical diagnosis.

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  • 6.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Mohammad, Aladdin J.
    Department of Clinical Sciences/Rheumatology, Lund University, Lund, Sweden, and Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Gjertsson, Inger
    Department of Rheumatology and Inflammation Research, Gothenburg University, Gothenburg, Sweden.
    Alexeyenko, Andrey
    Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, and Evi-networks, Stockholm, Sweden.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Protein profiling in presymptomatic individuals separates myeloperoxidase-antineutrophil cytoplasmic antibody and proteinase 3-antineutrophil cytoplasmic antibody vasculitides2023In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 75, no 6, p. 996-1006Article in journal (Refereed)
    Abstract [en]

    Objective: Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a chronic relapsing condition with unknown etiology. To gain insight into the molecular processes underlying the disease, we examined biomarkers in blood samples collected prior to symptom onset.

    Methods: The National Patient Register and Cause of Death register were searched for AAV-related International Classification of Diseases, Ninth Revision and Tenth Revision codes and linked to the registers from 5 biobanks. Eighty-five AAV patients with samples predating symptom onset of AAV were identified. For each case of AAV, 2 matched controls were included. Proteinase 3 (PR3)–ANCA and myeloperoxidase (MPO)–ANCA expression levels were analyzed using enzyme-linked immunosorbent assays. Using an Olink Inflammation panel, 73 of 92 proteins were included after quality control. Data were replicated in a second cohort of 48 presymptomatic individuals and 96 controls.

    Results: Of the 20 proteins with the lowest P values in the original cohort, 7 were replicated in the second cohort and 5 proteins were found to be significant between the groups in a meta-analysis. Eleven different pathways were identified in network enrichment analyses and were found to be significant in both cohorts. Stratification of samples obtained ≤5 years before symptom onset showed significant levels of CCL23, vascular endothelial growth factor A, and hepatocyte growth factor, which were also increased at borderline significant levels in the replication cohort (interleukin-6 was found to be significantly increased in the replication cohort). In presymptomatic AAV patients, 6 proteins were associated with MPO-ANCA positivity, and 7 proteins were associated with PR3-ANCA positivity.

    Conclusion: To our knowledge, this is the first study to identify protein markers preceding symptom onset in AAV patients. These findings set the stage for further research into the underlying cellular and molecular mechanisms in the pathogenesis of AAV and the diversification of patients into PR3-ANCA+ and MPO-ANCA+ subphenotypes. (Figure presented.).

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  • 7.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alexeyenko, Andrey
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Protein Profiling and Network Enrichment Analysis in Individuals Before and After the Onset of Rheumatoid Arthritis2019In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 71Article in journal (Other academic)
  • 8.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Alexeyenko, Andrey
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Protein profiling and network enrichment analysis in individuals before and after the onset of rheumatoid arthritis2019In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 21, no 1, article id 288Article in journal (Refereed)
    Abstract [en]

    Background: Antibodies and upregulated cytokines and chemokines predate the onset of rheumatoid arthritis (RA) symptoms. We aimed to identify the pathways related to the early processes leading to RA development, as well as potential novel biomarkers, using multiple protein analyses.

    Methods: A case-control study was conducted within the Biobank of northern Sweden. The plasma samples from 118 pre-symptomatic individuals (207 samples; median predating time 4.1 years), 79 early RA patients, and 74 matched controls were analyzed. The levels of 122 unique proteins with an acknowledged relationship to autoimmunity were analyzed using 153 antibodies and a bead-based multiplex system (FlexMap3D; Luminex Corp.). The data were analyzed using multifactorial linear regression model, random forest, and network enrichment analysis (NEA) based on the 10 most significantly differentially expressed proteins for each two-by-two group comparison, using the MSigDB collection of hallmarks.

    Results: There was a high agreement between the different statistical methods to identify the most significant proteins. The adipogenesis and interferon alpha response hallmarks differentiated pre-symptomatic individuals from controls. These two hallmarks included proteins involved in innate immunity. Between pre-symptomatic individuals and RA patients, three hallmarks were identified as follows: apical junction, epithelial mesenchymal transition, and TGF-beta signaling, including proteins suggestive of cell interaction, remodulation, and fibrosis. The adipogenesis and heme metabolism hallmarks differentiated RA patients from controls.

    Conclusions: We confirm the importance of interferon alpha signaling and lipids in the early phases of RA development. Network enrichment analysis provides a tool for a deeper understanding of molecules involved at different phases of the disease progression.

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  • 9. Davies, G.
    et al.
    Armstrong, N.
    Bis, J. C.
    Bressler, J.
    Chouraki, V.
    Giddaluru, S.
    Hofer, E.
    Ibrahim-Verbaas, C. A.
    Kirin, M.
    Lahti, J.
    van der Lee, S. J.
    Le Hellard, S.
    Liu, T.
    Marioni, R. E.
    Oldmeadow, C.
    Postmus, I.
    Smith, A. V.
    Smith, J. A.
    Thalamuthu, A.
    Thomson, R.
    Vitart, V.
    Wang, J.
    Yu, L.
    Zgaga, L.
    Zhao, W.
    Boxall, R.
    Harris, S. E.
    Hill, W. D.
    Liewald, D. C.
    Luciano, M.
    Adams, H.
    Ames, D.
    Amin, N.
    Amouyel, P.
    Assareh, A. A.
    Au, R.
    Becker, J. T.
    Beiser, A.
    Berr, C.
    Bertram, L.
    Boerwinkle, E.
    Buckley, B. M.
    Campbell, H.
    Corley, J.
    De Jager, P. L.
    Dufouil, C.
    Eriksson, J. G.
    Espeseth, T.
    Faul, J. D.
    Ford, I.
    Gottesman, R. F.
    Griswold, M. E.
    Gudnason, V.
    Harris, T. B.
    Heiss, G.
    Hofman, A.
    Holliday, E. G.
    Huffman, J.
    Kardia, S. L. R.
    Kochan, N.
    Knopman, D. S.
    Kwok, J. B.
    Lambert, J-C
    Lee, T.
    Li, G.
    Li, S-C
    Loitfelder, M.
    Lopez, O. L.
    Lundervold, A. J.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Mather, K. A.
    Mirza, S. S.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Oostra, B. A.
    Palotie, A.
    Papenberg, G.
    Pattie, A.
    Petrovic, K.
    Polasek, O.
    Psaty, B. M.
    Redmond, P.
    Reppermund, S.
    Rotter, J. I.
    Schmidt, H.
    Schuur, M.
    Schofield, P. W.
    Scott, R. J.
    Steen, V. M.
    Stott, D. J.
    Van Swieten, J. C.
    Taylor, K. D.
    Trollor, J.
    Trompet, S.
    Uitterlinden, A. G.
    Weinstein, G.
    Widen, E.
    Windham, B. G.
    Jukema, J. W.
    Wright, A. F.
    Wright, M. J.
    Yang, Q.
    Amieva, H.
    Attia, J. R.
    Bennett, D. A.
    Brodaty, H.
    de Craen, A. J. M.
    Hayward, C.
    Ikram, M. A.
    Lindenberger, U.
    Nilsson, Lars-Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). ARC, Karolinska Institutet, Stockholm.
    Porteous, D. J.
    Raikkonen, K.
    Reinvang, I.
    Rudan, I.
    Sachdev, P. S.
    Schmidt, R.
    Schofield, P. R.
    Srikanth, V.
    Starr, J. M.
    Turner, S. T.
    Weir, D. R.
    Wilson, J. F.
    Van Duijn, C.
    Launer, L.
    Fitzpatrick, A. L.
    Seshadri, S.
    Jr, T. H. Mosley
    Deary, I. J.
    Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)2015In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 20, no 2, p. 183-192Article in journal (Refereed)
    Abstract [en]

    General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health-and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N = 53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P = 3.93 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N = 6617) and the Health and Retirement Study (N = 5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e. = 5%) and 28% (s.e. = 7%), respectively. Using polygenic prediction analysis, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

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  • 10. Davies, Gail
    et al.
    Lam, Max
    Harris, Sarah E.
    Trampush, Joey W.
    Luciano, Michelle
    Hill, W. David
    Hagenaars, Saskia P.
    Ritchie, Stuart J.
    Marioni, Riccardo E.
    Fawns-Ritchie, Chloe
    Liewald, David C. M.
    Okely, Judith A.
    Ahola-Olli, Ari V.
    Barnes, Catriona L. K.
    Bertram, Lars
    Bis, Joshua C.
    Burdick, Katherine E.
    Christoforou, Andrea
    DeRosse, Pamela
    Djurovic, Srdjan
    Espeseth, Thomas
    Giakoumaki, Stella
    Giddaluru, Sudheer
    Gustavson, Daniel E.
    Hayward, Caroline
    Hofer, Edith
    Ikram, M. Arfan
    Karlsson, Robert
    Knowles, Emma
    Lahti, Jari
    Leber, Markus
    Li, Shuo
    Mather, Karen A.
    Melle, Ingrid
    Morris, Derek
    Oldmeadow, Christopher
    Palviainen, Teemu
    Payton, Antony
    Pazoki, Raha
    Petrovic, Katja
    Reynolds, Chandra A.
    Sargurupremraj, Muralidharan
    Scholz, Markus
    Smith, Jennifer A.
    Smith, Albert V.
    Terzikhan, Natalie
    Thalamuthu, Anbupalam
    Trompet, Stella
    van der Lee, Sven J.
    Ware, Erin B.
    Windham, B. Gwen
    Wright, Margaret J.
    Yang, Jingyun
    Yu, Jin
    Ames, David
    Amin, Najaf
    Amouyel, Philippe
    Andreassen, Ole A.
    Armstrong, Nicola J.
    Assareh, Amelia A.
    Attia, John R.
    Attix, Deborah
    Avramopoulos, Dimitrios
    Bennett, David A.
    Boehmer, Anne C.
    Boyle, Patricia A.
    Brodaty, Henry
    Campbell, Harry
    Cannon, Tyrone D.
    Cirulli, Elizabeth T.
    Congdon, Eliza
    Conley, Emily Drabant
    Corley, Janie
    Cox, Simon R.
    Dale, Anders M.
    Dehghan, Abbas
    Dick, Danielle
    Dickinson, Dwight
    Eriksson, Johan G.
    Evangelou, Evangelos
    Faul, Jessica D.
    Ford, Ian
    Freimer, Nelson A.
    Gao, He
    Giegling, Ina
    Gillespie, Nathan A.
    Gordon, Scott D.
    Gottesman, Rebecca F.
    Griswold, Michael E.
    Gudnason, Vilmundur
    Harris, Tamara B.
    Hartmann, Annette M.
    Hatzimanolis, Alex
    Heiss, Gerardo
    Holliday, Elizabeth G.
    Joshi, Peter K.
    Kahonen, Mika
    Kardia, Sharon L. R.
    Karlsson, Ida
    Kleineidam, Luca
    Knopman, David S.
    Kochan, Nicole A.
    Konte, Bettina
    Kwok, John B.
    Le Hellard, Stephanie
    Lee, Teresa
    Lehtimaki, Terho
    Li, Shu-Chen
    Liu, Tian
    Koini, Marisa
    London, Edythe
    Longstreth, Will T., Jr.
    Lopez, Oscar L.
    Loukola, Anu
    Luck, Tobias
    Lundervold, Astri J.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lyytikainen, Leo-Pekka
    Martin, Nicholas G.
    Montgomery, Grant W.
    Murray, Alison D.
    Need, Anna C.
    Noordam, Raymond
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ollier, William
    Papenberg, Goran
    Pattie, Alison
    Polasek, Ozren
    Poldrack, Russell A.
    Psaty, Bruce M.
    Reppermund, Simone
    Riedel-Heller, Steffi G.
    Rose, Richard J.
    Rotter, Jerome I.
    Roussos, Panos
    Rovio, Suvi P.
    Saba, Yasaman
    Sabb, Fred W.
    Sachdev, Perminder S.
    Satizabal, Claudia L.
    Schmid, Matthias
    Scott, Rodney J.
    Scult, Matthew A.
    Simino, Jeannette
    Slagboom, P. Eline
    Smyrnis, Nikolaos
    Soumare, Aicha
    Stefanis, Nikos C.
    Stott, David J.
    Straub, Richard E.
    Sundet, Kjetil
    Taylor, Adele M.
    Taylor, Kent D.
    Tzoulaki, Ioanna
    Tzourio, Christophe
    Uitterlinden, Andre
    Vitart, Veronique
    Voineskos, Aristotle N.
    Kaprio, Jaakko
    Wagner, Michael
    Wagner, Holger
    Weinhold, Leonie
    Wen, K. Hoyan
    Widen, Elisabeth
    Yang, Qiong
    Zhao, Wei
    Adams, Hieab H. H.
    Arking, Dan E.
    Bilder, Robert M.
    Bitsios, Panos
    Boerwinkle, Eric
    Chiba-Falek, Ornit
    Corvin, Aiden
    De Jager, Philip L.
    Debette, Stephanie
    Donohoe, Gary
    Elliott, Paul
    Fitzpatrick, Annette L.
    Gill, Michael
    Glahn, David C.
    Hagg, Sara
    Hansell, Narelle K.
    Hariri, Ahmad R.
    Ikram, M. Kamran
    Jukema, J. Wouter
    Vuoksimaa, Eero
    Keller, Matthew C.
    Kremen, William S.
    Launer, Lenore
    Lindenberger, Ulman
    Palotie, Aarno
    Pedersen, Nancy L.
    Pendleton, Neil
    Porteous, David J.
    Raikkonen, Katri
    Raitakari, Olli T.
    Ramirez, Alfredo
    Reinvang, Ivar
    Rudan, Igor
    Rujescu, Dan
    Schmidt, Reinhold
    Schmidt, Helena
    Schofield, Peter W.
    Schofield, Peter R.
    Starr, John M.
    Steen, Vidar M.
    Trollor, Julian N.
    Turner, Steven T.
    Van Duijn, Cornelia M.
    Villringer, Arno
    Weinberger, Daniel R.
    Weir, David R.
    Wilson, James F.
    Malhotra, Anil
    McIntosh, Andrew M.
    Gale, Catharine R.
    Seshadri, Sudha
    Mosley, Thomas H., Jr.
    Bressler, Jan
    Lencz, Todd
    Deary, Ian J.
    Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function2018In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 2098Article in journal (Refereed)
    Abstract [en]

    General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

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  • 11.
    Ekman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Domellöf, Magdalena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Elgh, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Longitudinal changes in task-evoked brain responses in Parkinson's disease patients with and without mild cognitive impairment2014In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 8, article id 207Article in journal (Refereed)
    Abstract [en]

    Cognitive deficits are common in Parkinson's disease. Previous cross-sectional research has demonstrated a link between cognitive impairments and fronto-striatal dopaminergic dysmodulation. However, longitudinal studies that link disease progression with altered task-evoked brain activity are lacking. Therefore, our objective was to longitudinally evaluate working-memory related brain activity changes in Parkinson's disease patients with and without mild cognitive impairment (MCI). Patients were recruited within a longitudinal cohort study of incident patients with idiopathic parkinsonism. We longitudinally (at baseline examination and at 12-months follow-up) compared 28 patients with Parkinson's disease without MCI with 11 patients with Parkinson's disease and MCI. Functional MRI blood oxygen level dependent signal was measured during a verbal two-back working-memory task. Patients with MCI under-recruited bilateral medial prefrontal cortex at both time-points (main effect of group: p < 0.001, uncorrected). Critically, a significant group-by-time interaction effect (p < 0.001, uncorrected) was found in the right fusiform gyrus, indicating that working-memory related activity decreased for patients with Parkinson's disease and MCI between baseline and follow-up, while patients without MCI were stable across time-points. The functional connectivity between right fusiform gyrus and bilateral caudate nucleus was stronger for patients without MCI relative to patients with MCI. Our findings support the view that deficits in working-memory updating are related to persistent fronto-striatal under-recruitments in patients with early phase Parkinson's disease and MCI. The longitudinal evolution of MCI in Parkinson's disease translates into additional task-evoked posterior cortical changes.

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  • 12.
    Eriksson, Staffan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Lundquist, Anders
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Lundin-Olsson, Lillemor
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Comparison of three statistical methods for analysis of fall predictors in people with dementia: negative binomial regression (NBR), regression tree (RT), and partial least squares regression (PLSR)2009In: Archives of gerontology and geriatrics (Print), ISSN 0167-4943, E-ISSN 1872-6976, Vol. 49, no 3, p. 383-389Article in journal (Refereed)
    Abstract [en]

    Searching for background factors associated with falls in people with dementia is difficult because the population is heterogeneous. The aim of this study was to compare the efficacies of three statistical methods for analysis of fall predictors in people with dementia. NBR, RT and PLSR analyses were compared. Data used for the comparison were from a prospective cohort study of 192 patients at a psychogeriatric ward, specializing in patients with cognitive impairment and related behavioral and psychological symptoms. Seventy-eight of these patients fell a total of 238 times. PLSR and RT analyses are directed at finding patterns among predictor variables related to outcome, whereas an NBR model is directed at finding predictor variables that, independent of other variables, are related to the outcome. The NBR analysis explained an additional 10–15% variation compared with the PLSR and RT analyses. The results of PLSR and RT show a similar plausible pattern of predictor variables. However, none of these techniques appears to be sufficient in itself. In order to gain patterns of explanatory variables, RT would be a good complement to NBR for analysis of fall predictors.

  • 13.
    Erlandsson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Otorhinolaryngology, University Hospital of Umeå, Umeå, Sweden.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE).
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Mapping quality of life after balloon dilatation in subglottic stenosis using Dyspnea index and Short Form Health Survey-362024In: European Archives of Oto-Rhino-Laryngology, ISSN 0937-4477, E-ISSN 1434-4726Article in journal (Refereed)
    Abstract [en]

    Purpose: An accurate diagnosis and proper treatment plan are required to restore an adequate patent airway in fibrotic subglottic stenosis (SGS). Currently, the definitive treatment entails single-stage balloon dilatation with steroid injections. The primary aim was to evaluate successful airway restoration and general quality of life in cases with SGS in northern Sweden using robust patient reported outcomes.

    Methods: All participants with need of surgical treatment due to SGS that had been referred to the department of otorhinolaryngology, University Hospital of Umeå from September 2020 to August 2023 was included. Exclusion criteria included malignant, extrathoracic or cartilaginous cause, age < 18 years, or incompetent to sign consent documents. We assessed the patient-reported outcome measures pre- as well as 3 months postoperatively.

    Results: Of the 40 cases fulfilling the eligibility criteria’s, 33 cases completed the Dyspnea index (DI) and the short form health survey (SF-36) pre- as well as 3 months post-operatively. Receiver operating characteristics showed significant improvement in DI as well as in SF 36 scores post-operatively.

    Conclusions: Evaluation of balloon dilatation in SGS in this cohort follow-up analysis shows clear improvement in patient quality of life using robust PROM 3 months postoperatively, ensuring the use of a safe and well-tolerated procedure.

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  • 14. Giddaluru, Sudheer
    et al.
    Espeseth, Thomas
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institutet and Stockholm University, 11330 Stockholm, Sweden.
    Westlye, Lars T
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Christoforou, Andrea
    Cichon, Sven
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Steen, Vidar M
    Reinvang, Ivar
    Nilsson, Lars Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). ARC, Karolinska Institutet, Stockholm, Sweden.
    Le Hellard, Stéphanie
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Genetics of structural connectivity and information processing in the brain2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 9, p. 4643-4661Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10(-08)). Suggestive associations (Meta P value <1 × 10(-06)) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10(-08)). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10(-07)). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10(-08)), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10(-07)) and the multimodal analysis (Fisher P value = 1 × 10(-07)). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.

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  • 15.
    Gomez-Bañuelos, Eduardo
    et al.
    John Hopkins University, Baltimore United states.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Konig, Maximilian F.
    John Hopkins University, Baltimore, United States.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Paz, Merlin
    John Hopkins University, Baltimore, United States.
    Buhlin, Kåre
    Karolinska institutet, Stockholm, Sweden.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Andrade, Felipe
    John Hopkins University, Baltimore, United States.
    Exposure to Aggregatibacter Actinomycetemcomitans before Symptom Onset and the Risk of Evolving to Rheumatoid Arthritis2020In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 9, no 6, article id 1906Article in journal (Refereed)
    Abstract [en]

    Periodontal disease has been implicated in the pathogenesis of rheumatoid arthritis (RA), an autoimmune disease characterized by immune-mediated synovial damage, and antibodies to citrullinated antigens. Here, we investigate the association between exposure to the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) and the development of RA. IgM, IgG and IgA antibodies to Aa leukotoxin A (LtxA) were detected by ELISA in plasma from a cohort of Swedish adults at different stages of RA development, from before onset of symptoms to established disease. Patients with early and established RA had increased levels of anti-LtxA IgM compared with matched non-RA controls and periodontally healthy individuals. Logistic regression revealed that anti-LtxA IgM levels were associated with RA during early disease (OR 1.012, 95%CI 1.007, 1.017), which was maintained after adjustment for smoking, anti-CCP antibodies, rheumatoid factor, HLA-DRB1 shared epitope alleles and sex. We found no association between anti-LtxA IgG/IgA antibodies and RA at any stage of disease development. The data support a temporal association between anti-LtxA IgM antibodies and the development of RA, suggesting that a subset of RA patients may have been exposed to Aa around the time of transition from being asymptomatic to become a patient with RA.

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  • 16.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    A Hierarchical Bayesian Mixture Model Approach for Analysis of Resting-State Functional Brain Connectivity: An Alternative to Thresholding2020In: Brain Connectivity, ISSN 2158-0014, E-ISSN 2158-0022, Vol. 10, no 5, p. 202-211Article in journal (Refereed)
    Abstract [en]

    This article proposes a Bayesian hierarchical mixture model to analyze functional brain connectivity where mixture components represent "positively connected" and "non-connected" brain regions. Such an approach provides a data-informed separation of reliable and spurious connections in contrast to arbitrary thresholding of a connectivity matrix. The hierarchical structure of the model allows simultaneous inferences for the entire population as well as for each individual subject. A new connectivity measure, the posterior probability of a given pair of brain regions of a specific subject to be connected given the observed correlation of regions' activity, can be computed from the model fit. The posterior probability reflects the connectivity of a pair of regions relative to the overall connectivity pattern of an individual, which is overlooked in traditional correlation analyses. This article demonstrates that using the posterior probability might diminish the effect of spurious connections on inferences, which is present when a correlation is used as a connectivity measure. In addition, simulation analyses reveal that the sparsification of the connectivity matrix using the posterior probabilities might outperform the absolute thresholding based on correlations. Therefore, we suggest that posterior probability might be a beneficial measure of connectivity compared with the correlation. The applicability of the introduced method is exemplified by a study of functional resting-state brain connectivity in older adults.

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  • 17.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden; .
    A Hierarchical Bayesian Mixture Modeling Approach for Analysis of Resting-State Functional Brain Connectivity: An Alternative to ThresholdingManuscript (preprint) (Other academic)
  • 18.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden..
    Bayesian mixture modeling for longitudinal fMRI connectivity studies with dropoutManuscript (preprint) (Other academic)
  • 19.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Longitudinal association between hippocampus atrophy and episodic-memory decline2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 51, p. 167-176Article in journal (Refereed)
    Abstract [en]

    There is marked variability in both onset and rate of episodic-memory decline in aging. Structural magnetic resonance imaging studies have revealed that the extent of age-related brain changes varies markedly across individuals. Past studies of whether regional atrophy accounts for episodic-memory decline in aging have yielded inconclusive findings. Here we related 15-year changes in episodic memory to 4-year changes in cortical and subcortical gray matter volume and in white-matter connectivity and lesions. In addition, changes in word fluency, fluid IQ (Block Design), and processing speed were estimated and related to structural brain changes. Significant negative change over time was observed for all cognitive and brain measures. A robust brain-cognition change-change association was observed for episodic-memory decline and atrophy in the hippocampus. This association was significant for older (65-80 years) but not middle-aged (55-60 years) participants and not sensitive to the assumption of ignorable attrition. Thus, these longitudinal findings highlight medial-temporal lobe system integrity as particularly crucial for maintaining episodic-memory functioning in older age. 

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  • 20. Hagg, S.
    et al.
    Zhan, Y.
    Karlsson, R.
    Gerritsen, L.
    Ploner, A.
    van der Lee, S. J.
    Broer, L.
    Deelen, J.
    Marioni, R. E.
    Wong, A.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Zhu, G.
    Hansell, N. K.
    Sillanpaa, E.
    Fedko, I. O.
    Amin, N. A.
    Beekman, M.
    de Craen, A. J. M.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Harris, S. E.
    Kan, K-J
    Martin-Ruiz, C. M.
    Montgomery, G. W.
    Adolfsson, Annelie N.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Reynolds, C. A.
    Samani, N. J.
    Suchiman, H. E. D.
    Viljanen, A.
    von Zglinicki, T.
    Wright, M. J.
    Hottenga, J-J
    Boomsma, D. I.
    Rantanen, T.
    Kaprio, J. A.
    Nyholt, D. R.
    Martin, N. G.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Kuh, D.
    Starr, J. M.
    Deary, I. J.
    Slagboom, P. E.
    van Duijn, C. M.
    Codd, V.
    Pedersen, N. L.
    Short telomere length is associated with impaired cognitive performance in European ancestry cohorts2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, article id e1100Article in journal (Refereed)
    Abstract [en]

    The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 +/- 8.8 years) provided results for associations between qPCR-measuredTL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta = 0.051 per s. d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (beta = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (beta = -0.053; 95% CI: -0.087, -0.018; P = 0.003). Effects for DSST were stronger in APOE epsilon 4 non-carriers (beta = 0.081; 95% CI: 0.045, 0.117; P = 1.0 x 10(-5)), whereas carriers performed better in STROOP (beta = -0.074; 95% CI: -0.140, -0.009; P = 0.03). Causal associations were found for STROOP only (beta = -0.598 per s. d.-increase of TL; 95% CI: -1.125, -0.072; P = 0.026), with a larger effect in epsilon 4-carriers (beta = -0.699; 95% CI: -1.330, -0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE epsilon 4-carriers might be at differential risk.

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  • 21.
    Harrefors, Christina
    et al.
    Institutionen för Hälsovetenskap, Luleå Tekniska Universitet.
    Sävenstedt, Stefan
    Institutionen för Hälsovetenskap, Luleå Tekniska Universitet.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Bengt
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Axelsson, Karin
    Institutionen för Hälsovetenskap, Luleå Tekniska Universitet.
    Professional caregivers' perceptions on how persons with mild dementia might experience the usage of a digital photo diary2012In: Open Nursing Journal, E-ISSN 1874-4346, Vol. 6, p. 20-29Article in journal (Refereed)
    Abstract [en]

    Cognitive impairments influence the possibility of persons with dementia to remember daily events and maintain a sense of self. In order to address these problems a digital photo diary was developed to capture information about events in daily life. The device consisted of a wearable digital camera, smart phone with Global Positioning System (GPS) and a home memory station with computer for uploading the photographs and touch screen. The aim of this study was to describe professional caregiver's perceptions on how persons with mild dementia might experience the usage of this digital photo diary from both a situation when wearing the camera and a situation when viewing the uploaded photos, through a questionnaire with 408 respondents. In order to catch the professional caregivers' perceptions a questionnaire with the semantic differential technique was used and the main question was "How do you think Hilda (the fictive person in the questionnaire) feels when she is using the digital photo diary?". The factor analysis revealed three factors; Sense of autonomy, Sense of self-esteem and Sense of trust. An interesting conclusion that can be drawn is that professional caregivers had an overall positive view of the usage of digital photo diary as supporting autonomy for persons with mild dementia. The meaningfulness of each situation when wearing the camera and viewing the uploaded pictures to be used in two different situations and a part of an integrated assistive device has to be considered separately. Individual needs and desires of the person who is living with dementia and the context of each individual has to be reflected on and taken into account before implementing assistive digital devices as a tool in care.

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  • 22.
    Johansson, Jarkko
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet & Stockholm University, Gavlegatan € 16, S11330, Stockholm, Sweden .
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Longitudinal evidence that reduced hemispheric encoding/retrieval asymmetry predicts episodic-memory impairment in aging2020In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 137, article id 107329Article in journal (Refereed)
    Abstract [en]

    The HERA (Hemispheric Encoding/Retrieval Asymmetry) model captures hemispheric lateralization of prefrontal cortex (PFC) brain activity during memory encoding and retrieval. Reduced HERA has been observed in cross-sectional aging studies, but there is no longitudinal evidence, to our knowledge, on age-related changes in HERA and whether maintained or reduced HERA relates to well-preserved memory functioning. In the present study we set out to explore HERA in a longitudinal neuroimaging sample from the Betula study [3 Waves over 10 years; Wave-1: n = 363, W2: n = 227, W3: n = 101]. We used fMRI data from a face-name paired-associates task to derive a HERA index. In support of the HERA model, the mean HERA index was positive across the three imaging waves. The longitudinal age-HERA relationship was highly significant (p < 10(-11)), with a HERA decline occurring after age 60. The age-related HERA decline was associated with episodic memory decline (p < 0.05). Taken together, the findings provide large-scale support for the HERA model, and suggest that reduced HERA in the PFC reflects pathological memory aging possibly related to impaired ability to bias mnemonic processing according to the appropriate encoding or retrieval state.

  • 23.
    Johansson, Jarkko
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Brandmaier, Andreas M.
    Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, D-14195 Berlin, Germany; Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin Germany and London, UK .
    Lindenberger, Ulman
    Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, D-14195 Berlin, Germany; Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin Germany and London, UK .
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Model of brain maintenance reveals specific change-change association between medial-temporal lobe integrity and episodic memory2022In: Aging Brain, Vol. 2, article id 100027Article in journal (Refereed)
    Abstract [en]

    Brain maintenance has been identified as a major determinant of successful memory aging. However, the extent to which brain maintenance in support of successful memory aging is specific to memory-related brain regions or forms part of a brain-wide phenomenon is unresolved. Here, we used longitudinal brain-wide gray matter MRI volumes in 262 healthy participants aged 55 to 80 years at baseline to investigate separable dimensions of brain atrophy, and explored the links of these dimensions to different dimensions of cognitive change. We statistically adjusted for common causes of change in both brain and cognition to reveal a potentially unique signature of brain maintenance related to successful memory aging. Critically, medial temporal lobe (MTL)/hippocampal change and episodic memory change were characterized by unique, residual variance beyond general factors of change in brain and cognition, and a reliable association between these two residualized variables was established (r = 0.36, p < 0.01). The present study is the first to provide solid evidence for a specific association between changes in (MTL)/hippocampus and episodic memory in normal human aging. We conclude that hippocampus-specific brain maintenance relates to the specific preservation of episodic memory in old age, in line with the notion that brain maintenance operates at both general and domain-specific levels.

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  • 24.
    Jonasson, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Kramer, Arthur
    Departments of Psychology and Mechanical and Industrial Engineering, Northeastern University, Boston, MA, USA.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Boraxbekk, Carl-Johan
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark.
    Aerobic Exercise Intervention, CognitivePerformance, and Brain Structure: results from the Physical Influences on Brain in Aging (PHIBRA) Study2017In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 8, p. 1-15, article id 336Article in journal (Refereed)
    Abstract [en]

    Studies have shown that aerobic exercise has the potential to improve cognition and reduce brain atrophy in older adults. However, the literature is equivocal with regards to the specificity or generality of these effects. To this end, we report results on cognitive function and brain structure from a 6-month training intervention with 60 sedentary adults (64–78 years) randomized to either aerobic training or stretching and toning control training. Cognitive functions were assessed with a neuropsychological test battery in which cognitive constructs were measured using several different tests. Freesurfer was used to estimate cortical thickness in frontal regions and hippocampus volume. Results showed that aerobic exercisers, compared to controls, exhibited a broad, rather than specific, improvement in cognition as indexed by a higher “Cognitive score,” a composite including episodic memory, processing speed, updating, and executive function tasks (p = 0.01). There were no group differences in cortical thickness, but additional analyses revealed that aerobic fitness at baseline was specifically related to larger thickness in dorsolateral prefrontal cortex (dlPFC), and hippocampus volume was positively associated with increased aerobic fitness over time. Moreover, “Cognitive score” was related to dlPFC thickness at baseline, but changes in “Cognitive score” and dlPFC thickness were associated over time in the aerobic group only. However, aerobic fitness did not predict dlPFC change, despite the improvement in “Cognitive score” in aerobic exercisers. Our interpretation of these observations is that potential exercise-induced changes in thickness are slow, and may be undetectable within 6-months, in contrast to change in hippocampus volume which in fact was predicted by the change in aerobic fitness. To conclude, our results add to a growing literature suggesting that aerobic exercise has a broad influence on cognitive functioning, which may aid in explaining why studies focusing on a narrower range of functions have sometimes reported mixed results.

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  • 25.
    Josefsson, Maria
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Imputation of missing longitudinal fMRI dataManuscript (preprint) (Other academic)
  • 26.
    Karlsson, Maria
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundin, Mathias
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Student active learning online and in the classroom by combining the best of Flipped Classroom and MOOCs when teaching statistics2017In: RSS International Conference: Abstract booklet, Royal Statistical Society , 2017, p. 18-18Conference paper (Other academic)
    Abstract [en]

    Flipped classroom teaching means, in short, to change/flip where students and teachers dothings. Instead of students (passively) listening to a teacher’s lecture in the classroom andthen going home to solve problems on their own, the idea is that students first watch video lectures at home and then come to the classroom to (actively) solve problems together with other students and the teacher.

    As part of a pedagogical project, we have used special learning management system (LMS)called “Scalable Learning”, which facilitates teaching with flipped classroom techniques. The Scalable Learning LMS allows the teacher to make the video lectures interactive by adding quizzes and surveys to the videos (as is very common in Massive Open Online Courses (MOOCs)), thereby helping the students to be more active while watching the videos. Moreover, there are different tools implemented in the LMS so that students e.g., can ask questions in direct connection to the videos. The student supplied questions and their answers to the quizzes can then, together with other data from the LMS, be used by theteacher to prepare classroom activities customized to the students’ needs.

    We present our experiences of teaching a course in statistics using this LMS; there are both pros and cons from a teachers’ point of view. Also, we present the students’ opinions with the LMS and with the flipped classroom teaching that they were exposed to during the course. Most of them were very satisfied with the concept but they also provided us with several interesting ideas on how to improve the course.

  • 27.
    Kauppi, Karolina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nilsson, Lars-Göran
    Stockholm University.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Elias
    Gothenburg University.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Decreased medial temporal lobe activation in BDNF 66Met allele carriers during memory encoding2013In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 51, no 12, p. 2462-2468Article in journal (Refereed)
    Abstract [en]

    The Met allele of the Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism has been associated with impaired activity-dependent secretion of BDNF protein and decreased memory performance. Results from imaging studies relating Val(66)Met to brain activation during memory processing have been inconsistent, with reports of both increased and decreased activation in the Medial Temporal Lobe (MTL) in Met carriers relative to Val homozygotes. Here, we extensively studied BDNF Val(66)Met in relation to brain activation and white matter integrity as well as memory performance in a large imaging (n=194) and behavioral (n=2229) sample, respectively. Functional magnetic resonance imaging (fMRI) was used to investigate MTL activation in healthy participants in the age of 55-75 years during a face-name episodic encoding and retrieval task. White matter integrity was measured using diffusion tensor imaging.

    BDNF Met allele carriers had significantly decreased activation in the MTL during encoding processes, but not during retrieval processes. In contrast to previous proposals, the effect was not modulated by age and the polymorphism was not related to white matter integrity. Met carriers had lower memory performance than Val homozygotes, but differences were subtle and not significant. In conclusion, the BDNF Met allele has a negative influence on MTL functioning, preferentially during encoding processes, which might translate into impaired episodic memory function.

  • 28. Kissel, Theresa
    et al.
    van Schie, Karin Anna
    Hafkenscheid, Lise
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wuhrer, Manfred
    Huizinga, Tom W. J.
    Scherer, Hans Ulrich
    Toes, Rene
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 12, p. 1616-1620Article in journal (Refereed)
    Abstract [en]

    Objective: Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N-linked glycans within the variable domains (V-domains). Recently, we showed that N-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients.

    Methods: ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative).

    Results: V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG.

    Conclusion: Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA.

  • 29. Kissel, Theresa
    et al.
    van Schie, Karin
    Hafkenscheid, Lise
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Scherer, Hans Ulrich
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Toes, Rene
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Rising ACPA igg variable domain glycosylation pre-disease associates with an increase in autoantibody levels and the development of rheumatoid arthritis2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, p. 249-250Article in journal (Other academic)
    Abstract [en]

    Background: Anti-citrullinated protein antibodies (ACPA) are present in the majority of rheumatoid arthritis (RA) patients (60-70%) and play a pivotal role in disease development1. ACPA IgGs are unique in a way that they are abundantly N-glycosylated within their variable regions2. These variable domain (V-domain) glycans are found on over 90% of ACPAs present in sera from RA-patients3. To undergo N-linked glycosylation, a consensus sequence in the protein backbone is required (N-X-S/T, where X ≠ P)4. Recently, it was shown that the N-linked glycosylation sites in ACPA-IgG V-domains are introduced during somatic hypermutation and that the introduction of such sites likely conveys a selective advantage to ACPA expressing B-cells5. However, it is currently unknown, whether ACPA-expressing B-cells already introduced glycosylation-sites into their V-domains before disease onset or when ACPA-V-domain glycosylation occurs.

    Objectives: Investigate the appearance of ACPA V-domain glycosylation in pre-symptomatic individuals and RA patients.

    Methods In a case-control study, individuals (n=201) from the Medical Biobank, who were sampled before onset of symptoms (mean±SEM predating time; 5.8±0.3 years) (140 aCCP+ and 61 aCCP-), and after diagnosis of RA (n=99, 94 aCCP+ and 5 aCCP-) and randomly selected control samples (n=43, 3 aCCP+ and 40 aCCP-) were analyzed for their ACPA IgG V-domain glycosylation levels. ACPA IgGs were affinity purified, N-linked glycans released, and 2-AA labeled for further analysis using UHPLC6. Data calibration and integration was performed and a cut-off defined. Samples below the cut-off were determined as non-detectable and excluded from the analysis. The percentage V-domain glycosylation was calculated as described previously3. Statistical calculations were performed using SPSS.

    Results: Our data indicated that ACPA IgG V-domain glycans are already present years before symptom onset, in pre-symptomatic individuals who subsequently will develop RA. Analysis of matched pairs showed a significant increase of ACPA V-domain glycosylation in RA patients compared to individuals pre-disease (p<0.001). The results showed that ACPA N-glycosylation was correlated with anti-CCP concentrations pre-disease (rs =0.504, p<0.001), while no such association can be found after RA onset. Further, V-domain glycosylation levels increase closer to symptom onset.

  • 30. Kissel, Theresa
    et al.
    Van Wesemael, Tineke J.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kawakami, Atsushi
    Tamai, Mami
    Van Schaardenburg, Dirkjan
    Wuhrer, Manfred
    Huizinga, Tom W.J.
    Scherer, Hans Ulrich
    Van Der Woude, Diane
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Toes, René E.M.
    Genetic predisposition (HLA-SE) is associated with ACPA-IgG variable domain glycosylation in the predisease phase of RA2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 16, p. 1-3Article in journal (Refereed)
  • 31.
    Koch, Elise
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.