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Structural brain changes in hyperthyroid Graves’ disease: protocol for an ongoing longitudinal, case-controlled study in Göteborg, Sweden—the CogThy project
  1. Mats Olof Holmberg1,2,
  2. Helge Malmgren2,3,
  3. Peter Berglund4,
  4. Lina Bunketorp-Käll5,
  5. Rolf A Heckemann6,7,
  6. Birgitta Johansson4,
  7. Niklas Klasson3,4,
  8. Erik Olsson2,
  9. Simon Skau3,4,
  10. Helena Nystrom Filipsson2,8
  1. 1 ANOVA, Karolinska University Hospital, Stockholm, Sweden
  2. 2 Institute of Medicine, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden
  3. 3 MedTech West, University of Gothenburg, Sahlgrenska University Hospital, Göteborg, Sweden
  4. 4 Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg, Sweden
  5. 5 Department of Health and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg, Sweden
  6. 6 Division of Brain Sciences, Department of Medicine, Faculty of Medicine, Imperial College London, London, UK
  7. 7 Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy, Göteborg, Sweden
  8. 8 Department of Endocrinology, Sahlgrenska University Hospital, Göteborg, Sweden
  1. Correspondence to Dr Mats Olof Holmberg; mats.holmberg{at}


Introduction Cognitive impairment and reduced well-being are common manifestations of Graves’ disease (GD). These symptoms are not only prevalent during the active phase of the disease but also often prevail for a long time after hyperthyroidism is considered cured. The pathogenic mechanisms involved in these brain-derived symptoms are currently unknown. The overall aim of the CogThy study is to identify the mechanism behind cognitive impairment to be able to recognise GD patients at risk.

Methods and analysis The study is a longitudinal, single-centre, case-controlled study conducted in Göteborg, Sweden on premenopausal women with newly diagnosed GD. The subjects are examined: at referral, at inclusion and then every 3.25 months until 15 months. Examinations include: laboratory measurements; eye evaluation; neuropsychiatric and neuropsychological testing; structural MRI of the whole brain, orbits and medial temporal lobe structures; functional near-infrared spectroscopy of the cerebral prefrontal cortex and self-assessed quality of life questionnaires. The primary outcome measure is the change in medial temporal lobe structure volume. Secondary outcome measures include neuropsychological, neuropsychiatric, hormonal and autoantibody variables. The study opened for inclusion in September 2012 and close for inclusion in October 2019. It will provide novel information on the effect of GD on medial temporal lobe structures and cerebral cortex functionality as well as whether these changes are associated with cognitive and affective impairment, hormonal levels and/or autoantibody levels. It should lead to a broader understanding of the underlying pathogenesis and future treatment perspectives.

Ethics and dissemination The study has been reviewed and approved by the Regional Ethical Review Board in Göteborg, Sweden. The results will be actively disseminated through peer-reviewed journals, national and international conference presentations and among patient organisations after an appropriate embargo time.

Trial registration number 44321 at the public project database for research and development in Västra Götaland County, Sweden (

  • Graves' disease
  • hippocampus
  • cognitive impairment
  • magnetic resonance volumetry
  • functional near-infrared spectroscopy
  • quality of life

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  • Contributors MOH has written the manuscript with input from all the other authors. HM is responsible for the statistics and has broad knowledge about mental syndromes. As a psychiatrist, PB will perform psychiatric evaluations and, as neuropsychologist, BJ will perform psychological testing. LB-K and SS will perform and evaluate fNIRS investigations, and EO, RAH and NK are responsible for volumetry evaluations. MOH is a PhD student in the project and will see all patients in collaboration with HNF, who is the principal investigator of the CogThy project.

  • Funding The following sponsors supported this study. The study was financed by grants from: the Swedish state under an agreement between the Swedish government and county councils, the ALF agreement (ALFGBG-717311); regional research funding, Region Västra Götaland; the Healthcare Sub-committee, Region Västra Götaland; the Healthcare Board, Region Västra Götaland; Sahlgrenska University Hospital research funds; the Gothenburg Medical Society; the Swedish Medical Society; the Swedish Society for Medical Research; The Swedish Endocrine Society; The Fredrik and Ingrid Thuring's Foundation; the Iris grant; the Jeanssons's Foundation; the Tore Nilsson's Foundation; the Wilhelm and Martina Lundgren's Foundation; the Pharmacist Hedberg's Foundation and the Åke Wiberg's Foundation. Siemens Healthineers has supported the study by providing reagents for TSI. The project is also supported by MedTech West ( ), a medical innovation and development platform initiated as a collaboration between Chalmers University of Technology, University of Borås, University of Gothenburg, Sahlgrenska University Hospital and Region Västra Götaland, Sweden. MedTech West provides office space for the project participants as well as laboratory space and meeting facilities for activities of the CogThy project. The supporting or funding bodies have no role in the study design, collection, analysis and interpretation of data, in manuscript writing or in the decision to submit the manuscript for publication.

  • Competing interests HNF has received lecture fees from Siemens Inc., AstraZeneca and Bristol-Myers Squibb.

  • Patient consent for publication Not required.

  • Ethics approval Ethical approval was granted by the Regional Ethical Review Board (Ref no. 190-10; approved 21 June 2010) in Göteborg, Sweden. The study is conducted according to the Declaration of Helsinki. The results will be actively disseminated through peer-reviewed journals, national and international conference presentations and among patient organisations after an appropriate embargo time. Preliminary data have been presented at: the Brain's Networks conference in Gothenburg 2015; the Annual Meeting of the European Thyroid Association in Copenhagen 2016; the Annual Meeting of the American Thyroid Association in Victoria, Canada 2017; the Annual Conference of the Swedish Endocrine Society 2017 and the American Thyroid Association Annual Meeting in Washington, USA, 2018.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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