Den autoimmuna hjärnan- ett nytt koncept vid Graves sjukdom
Den autoimmuna hjärnan- ett nytt koncept vid Graves sjukdom
Project number : 260071
Created by: Karin Tammelin, 2018-12-27
Last revised by: Karin Tammelin, 2018-12-28
Project created in: FoU i Västra Götalandsregionen

PublishedPublished

1. Översiktlig projektbeskrivning

Engelsk titel

The autoimmune brain- a new concept in Graves´disease

Populärvetenskaplig sammanfattning av projektet

Graves sjukdom är den i Sverige vanligaste formen av överfunktion i sköldkörteln med 2000 fall per år. Sjukdomen orsakas av antikroppar som stimulerar sköldkörteln till ökad hormonproduktion och är alltså en autoimmun sjukdom. Många drabbade får kvarstående besvär med psykisk utmattning vilket förekommer vid flera sjukdomar. Orsaken till detta är okänd men en annan vanlig komplikation till Graves sjukdom är s k endokrin oftalmopati orsakad av antikroppar mot strukturer i ögat. Detta projekt syftar till att i två faser undersöka om autoimmunitet även ligger bakom den psykiska utmattningen samt om denna kan förutsägas genom att

1) Identifiera autoimmuna biomarkörer i relation till mental trötthet: 310 patienter med Graves sjukdom får fylla i standardiserade frågeformulär för mental trötthet (Mental Fatigue scale) och för besvär av hypertyreos (ThyPro questionnaire) vid diagnos och efter 15 månader samt lämna blodprov för antikroppar, cytokiner och markörer för hjärnskada. Resultaten kommer att analyseras statistiskt för att finna relevanta biomarkörer.

2)  Identifiera förändringar i hjärnan länkade till mental trötthet: 65 andra patienter med Graves sjukdom än de undersökta enligt ovan kommer att vid diagnos och efter 15 månader testas för biomarkörer identifierade i projektets första fas. Blodflöde i samt volym hos olika delar av hjärnan kommer att undersökas med hjälp av magnetröntgen och deltagarna kommer att genomgå neuropsykologisk och psykiatrisk testning.

Vetenskaplig sammanfattning av projektet

Graves sjukdom (GS) drabbar i Sverige 2000/år och drivs av autoantikroppar mot TSH-receptorn. Hypertyreosen i sig orsakar symtom från många organsystem men komplikationer till Graves sjukdom är av autoimmun genes, varav den vanligaste är endokrin oftamlopati. En stor del av patienterna drabbas av kvarstående psykisk utmattning (mental fatigue MF).

MF förekommer vid många sjukdomar men orsaken är oftast okänd. Är kvarstående MF efter behandlad hypertyreos vid GS en autoimmun komplikation som kan förutsägas? Denna hypotes kommer att undersökas i två steg:

1) Identifiera autoimmuna biomarkörer i relation till mental trötthet: 310 patienter med Graves sjukdom får fylla i standardiserade frågeformulär för mental trötthet (Mental Fatigue scale) och för besvär av hypertyreos (ThyPro questionnaire) vid diagnos och efter 15 månader samt lämna blodprov för autoantikroppar mot G-proteinkopplade receptorer, VGKC, NMDAR, GAD, IGF-1,thyoglobulin, TPO och tyroxinreceptorn och för proinflammatoriska cytokiner (IL-6, IL-17, TNF-alfa) regulatoriska cytokiner (IL-10 och IL-31) och markörer för organisk hjärnskada (neurofilament och GFAP). Resultaten kommer att analyseras statistiskt för att finna relevanta biomarkörer.

2)  Identifiera förändringar i hjärnan länkade till mental trötthet: 65 andra patienter med Graves sjukdom än de undersökta enligt ovan kommer att vid diagnos och efter 15 månader testas för biomarkörer identifierade i projektets första fas. Blodflöde i samt volym hos olika delar av hjärnan kommer att undersökas med hjälp av funktionell magnetröntgen och deltagarna kommer att genomgå neuropsykologisk och psykiatrisk testning.

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva typ av studier

checked Longitudinella studier (Longitudinal Studies)
checked Multicenterstudie


(Only selected options are displayed. Click here to display all options)

MeSH-termer för att beskriva ämnesområdet

information Added MeSH terms
Graves Disease
A common form of hyperthyroidism with a diffuse hyperplastic GOITER. It is an autoimmune disorder that produces antibodies against the THYROID STIMULATING HORMONE RECEPTOR. These autoantibodies activate the TSH receptor, thereby stimulating the THYROID GLAND and hypersecretion of THYROID HORMONES. These autoantibodies can also affect the eyes (GRAVES OPHTHALMOPATHY) and the skin (Graves dermopathy).
Mental Fatigue
Fatigue arising in consequence of mental effort.
Autoimmunity
Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by AUTOIMMUNE DISEASES.

Projektets delaktighet i utbildning

checked Avhandling


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2. Projektorganisation och finansiering

Arbetsplatser involverade i projektet

information Added workplaces
Regioner - Västra Götalandsregionen - Specialiserad vård - Sahlgrenska Universitetssjukhuset - Område 6 - Medicin, Sahlgrenska workplace verified by Västra Götalandsregionen on 2018-02-27
Regioner - Västra Götalandsregionen - Specialiserad vård - Sahlgrenska Universitetssjukhuset - Område 2 - Medicin, Geriatrik och Akutmottagning Östra workplace verified by Västra Götalandsregionen on 2018-02-27
Regioner - Västra Götalandsregionen - Specialiserad vård - Sahlgrenska Universitetssjukhuset - Område 4 - Laboratoriemedicin - Klinisk immunologi och transfusionsmedicin workplace verified by Västra Götalandsregionen on 2018-02-27
Företag - Privata vårdgivande bolag - inom Västra Götalandsregionen - Specialiserad vård - Capio Lundby Närsjukhus workplace verified by Västra Götalandsregionen on 2018-02-27
Företag - Privata vårdgivande bolag - inom Västra Götalandsregionen - Specialiserad vård - Carlanderska sjukhuset workplace verified by Västra Götalandsregionen on 2018-02-27
Regioner - Västra Götalandsregionen - Specialiserad vård - Södra Älvsborgs sjukhus (SÄS) workplace verified by Västra Götalandsregionen on 2018-02-27

Coworker

Anna Lundgren
Biolog, forskare, Klinisk immunologi och transfusionsmedicin, Avdelningen för mikrobiologi och immunologi
Bengt Andersson
Läkare, Klinisk immunologi och transfusionsmedicin
Mats Holmberg
Specialistläkare, Alla områden
Clas Malmeström
Överläkare, Klinisk immunologi och transfusionsmedicin, Neurosjukvård
Ragnhildur Bergthorsdottir
Specialistläkare, Medicin, Sahlgrenska
Helge Malmgren
Emeritus professor, Institutionen för medicin
Lise-Lott Norrman
Överläkare, Medicin, Sahlgrenska
Kaj Stenlöf
Överläkare, Carlanderska sjukhuset

Tutor

Helena Filipsson Nyström
Docent, Universitetssjukhusöverläkare, Medicin, Sahlgrenska

Finansiering

Grants

regionala FoU-medel
250 000 SEK (applied sum: 485 000 SEK)
Karin Tammelin

2018, arbetskostnader, analyskostnader

Apotekare Hedbergs stiftelse (794)
75 000 SEK (applied sum: 75 000 SEK)
Helena Filipsson Nyström

2018,

Lisa och Johan Grönbergs stiftelse (2018-00133)
60 000 SEK (applied sum: 100 000 SEK)
Helena Filipsson Nyström

2018,

Svensk Sällskapet för medicinsk forskning (S18-0033)
0 SEK (applied sum: 5 200 000 SEK)
Helena Filipsson Nyström

,

3. Processen och projektets redovisning

Detaljerad projektbeskrivning

Beräknad projektstart

2018-11-01

Beräknat projektslut

2022-12-31

Projektsammanfattning

The goal of this research is to improve our ability to understand, diagnose, predict and prevent persistent brain dysfunction in Graves’ disease (GD). Specifically, it will focus on autoimmune effects on brain function and brain structures.

GD affects 2000 patients/ year in Sweden and is driven by autoantibodies. The hyperthyroidism per se entails symptom from many organ system, but known complications in GD are of autoimmune origin; the most frequent is thyroid associated ophtalmopathy. However, 37% of patients with successfully treated GD suffer from persistent mental fatigue (MF).

MF occur in many diseases and the reasons are mostly unknown.Is remaining MF after restored hyperthyroidism in GD actually an autoimmune complication that can be predicted? We have exciting data that strengthen our hypothesis that autoimmunity is a key role player. To test this hypothesis, we will pursue two specific aims:

  1. To identify autoimmune biomarkers in relation to MF At diagnosis and after 15 months, 310 GD patients will fill in the MF scale and leave blood samples for 16 autoantibodies, cytokines and markers for organic brain damage. Uni- and multivaiable logistic regression statistics will be used to select a subset of biomarkers linked to MF in GD.
  2. To determine brain changes linked to MF This will be tested in another GD cohort (n=65) in hyperthyroidism and 15 months later in euthyroidism compared to thyroid healthy controls. Methodology will involve the biomarkers selected from WP1, measurements of prefrontal blood flow and regional brain volumes, neuropsychology and psychiatry testing. The values of these variables from WP2 for adding independent predictive value are determined

This research may open up for a new concept in GD that may be applicable to other autoimmune disease and provide input for treatment studies. We are in a unique position to conduct this research, since our group combines competences matched by no other group.

Bakgrund

Graves’ disease (GD) is a chronic, systemic disease driven by autoantibodies (ab) stimulating the thyroid gland resulting in hyperthyroidism. It is common, affecting 21/100 000 persons per year, with a higher incidence in women (1). The hyperthyroidism per se entails symptom from many organ systems, but known complications in GD are of autoimmune origin; the most frequent and feared being thyroid associated ophtalmopathy (TAO) (Fig. 1).

Also, hyperthyroid patients have more affective symptoms, anxiety and cognitive dysfunction (2). An increased psychiatric morbidity is also detected before the diagnosis of GD (3). Recovery of wellbeing is delayed for months after euthyroidism. App 20% of patients with successfully treated GD suffer from persistent mental dysfunction 1 year after diagnosis (4), and many are not yet fully recovered even after 3 years or more (5,6).. The pathophysiological mechanism behind these deficits are poorly understood, and no evidence-based treatment approaches are available. This is frustrating for patients and relatives, as well as for treating clinicians.

The brain effects can be a result of intracerebral hyperthyroidism and/or by the autoimmunity per se (7). In hyperthyroidism, morphological changes in mature brain structures in comparison to controls are detected (8). The prefrontal and medio temporal lobes (MTL) are areas important for cognition.

We have preliminary data suggesting an autoimmune effect on brain function in GD.

This data are supported by observations that ab targeting thyroglobulin, tyreoperoxidase (TPO), insulin-like growth factor 1 receptor (IGF-1) (9), angiotensin II type 1 (AT1) (10), beta 1 adrenergic and M2 muscarinic receptors (11) are elevated in GD with proposed pathogenic effects. In fact, a new way to treat TAO with IGF-1 blocking ab was recently launched, which suggest a more vast autoimmune involvement in GD than previously thought.

Syfte

This project consists of three parts (work packages (WP)). I describe all WP so that you understand the overall purposes, but this application is only for the first study (WP1)

The ultimate goal of this research project is to improve our ability to understand, diagnose, predict and prevent persistent brain dysfunction in Graves’ disease.

To test the hypothesis, we will pursue the following specific aims:

  1. To identify any brain-related autoimmune biomarkers in blood that are linked to mental fatigue and low quality of life in Graves’ disease This will be done in a cohort of Graves’ patients (n=310) who are assessed for mental fatigue and quality of life at diagnosis and after 15 months of treatment. A panel of at least 16 autoimmune biomarkers will be analysed on both occasions. Univariable logistic regression will be used to identify significant predictors, and stepwise multivariable logistic regression analysis will be applied to select independent significant predictors (biomarkers).
  2. To determine functional and structural brain changes linked to mental fatigue in Graves’ disease This will be tested in a separate cohort of Graves’ patients (n=65) who are in hyperthyroidism at diagnosis and in euthyroidism after 15 months of treatment compared with matched, thyroid-healthy controls. The methodology will involve the selected autoimmune markers from the first study, physiological and anatomical measurements (blood flow in prefrontal cortex and regional brain volumetry), and behavioural assessments (neuropsychological and psychiatric testing). The best predictors from the first study are tested in the smaller cohort and the value of the physiological and anatomical variables for adding independent predictive value is determined.
  3. To formulate a tentative causal and predictive model for mental fatigue in Graves’ disease This model will be formulated as a Bayesian Network based on our general knowledge of neuropsychiatry, neuroendocrinology, and neuroimmunology. Data from the first two parts of the project, and other published data will be used as inputs to the model. The final model will be framed as a hypothesis to be validated in further studies.

If this project is successful, it will expand our knowledge on brain dysfunction in Graves’ patients. This knowledge may even be applicable to other autoimmune diseases. In addition, it may lead to new concepts in understanding patients with similar mental symptoms, but with no known autoimmune disease. It may also provide input for tailored mental interventions in Graves’ disease to prevent and/ or ameliorate mental fatigue.

We are in a unique position to conduct this research, since the group combines competences that are matched by no other group in the world, with experts in the fields of neuropsychology, psychiatry, endocrinology, immunology, biostatistics, structural and functional brain imaging

Frågeställning / Hypotes

We have preliminary data suggesting an autoimmune effect on brain function in Graves’ patients. This has led us to formulate the following hypothesis:

Persistent brain dysfunction following Graves’ disease is actually an autoimmune complication that can be detected, characterized, and predicted by measuring a set of biomarkers (fig 1).

Our previous results that support our hypothesis are:

  • 15 months after GD treatment, 37% GD patients are classified as having MF according to the MF Scale (MFS)
  • 25% of GD patients do not feel fully recovered 8 years after diagnosis, despite treatment
  • The levels of ab targeting G-protein coupled receptors (GPCRs), including the adrenergic and muscarinic acetylcholine receptors, are higher in GD than in healthy controls (Fig. 2b-c)
  • There is virtually no association between hippocampal volume, thyroid hormones, and TRAb at diagnosis when thyroid hormones are high
  • Hippocampal and amygdalar volumes are larger after 15 months of treatment than at diagnosis
  • In some GD patients, ab against the GPCR, angiotensin II receptor type I (anti-ATR1), increase from baseline to the 7.5 months visit (Fig 2a)
  • There is an inverse correlation between anti-ATR1 levels and bilateral hippocampal volume at diagnosis. AT1 is a well-known neurotransmitter (12)
  1. To identify any brain-related autoimmune biomarkers in blood that are linked to mental fatigue in GD
  2. Theory and Methods: Ab and proinflammatory cytokines can be produced in the CNS or reach the brain through the blood-brain-barrier, as the immune system has ways to penetrate (13). The pathological consequences of ab exposure can be reversible, as in limbic encephalitis, where ab target the voltage-gated potassium channel (VGKC) complex and the N-methyl D-aspartate receptor (NMDAR) on the neuronal cell surface, or irreversible (13). Other brain-derived super autoantigens have been proposed (14): glutamic acid decarboxylase (GAD) is associated with cognitive dysfunction in diabetes (15), ab targeting GPCRs are described in many autoimmune diseases, and α-1-adrenergic receptor ab cause cerebral vessel damage in Alzheimer’s disease (16). The acetylcholine receptor is responsible for synaptic transmissions that are crucial for cognitive function, and thyroglobulin ab recognize an acetylcholinesterase domain, and TPO ab bind to a sub-population of astrocytes (14).

Patients will be recruited at the Thyroid Unit at Sahlgrenska University Hospital (endocrinologist Helena Filipsson Nyström), but also at the Endocrine units at Sahlgrenska University Hospital/ Östra (PhD student Karin Tammeline ST in endocrinology) Lundby Hospital (endocrinologist Mariam Elbornsson), Carlanderska Hospital (endocrinologists Ragnhildur Bergthorsdottir and Kaj Stenlöf) and Southern Älvsborg’s Hospital (endocrinologist Lise-Lott Norrman). Although the Thyroid Unit is the largest unit in Gothenburg, including the three other units in Gothenburg limits selection bias and increase representability. For these matters, also the hospital in Borås is important as it is the eight largest city in Sweden and has referral from both urban and rural areas.

Consecutive patients (n=310) (adult (>18 years) men and women) with newly diagnosed GD (with overt hyperthyroidism (low TSH and elevated FT4) and positive TRAb and/ or diffuse uptake on technetium scintigraphy. The only exclusion criterion is patients who cannot attend to the protocol. Our goal is to have the patient information on the most common foreign languages used on the units. To sort that out we will look into the use of interpreters over the last year.

Power: In order to find a significant odds ratio of 1.50 per 1 SD increase in a predictor with power 80% for prediction of remaining mental fatigue in GD where 40% of patients have such fatigue, 250 evaluable patients are needed with logistic regression and two-sided test. Significance level 0.05. Estimating drop-outs to 20%, 310 patients are needed.

Metod: Intervention

Not applicable

Metod: Datainsamling

Study Design: Patients will fill in the mental fatigue scale (MFS) and ThyPro questionnaires, give background information (ethnicity, socioeconomic status, tobacco use, alcohol use, stress, pregnancies, family history, radiotherapy to the head and neck, head trauma, other diseases, and current medication), and leave blood for thyroid hormones, total TRAb and for biobanking at diagnosis and after 15 months in euthyroidism. Serum and plasma will be evaluated for a panel of at least 16 autoimmune biomarkers, a list that may be adjusted according to the literature at the time of analysis. In a subset similar markers will be analysed in cerebrospinal liquid. blood A subset biomarkers will be selected for further testing in WP 2.

The plan is to have the CRF and questionnaires electronically (collaboration with Medicase) and patients fill in their answers directly supported by the research nurse that will coordinate the study on all sites. In case it is easier locally, background information and questionnaires can be filled in on a paper sheet.

Methodology: We will focus on autoantibodies targeting GPCR, VGKC, NMDAR, GAD, IGF-I, thyroglobulin, and TPO, and TRAb using novel ELISA techniques. We will also determine the proinflammatory cytokines IL-6, IL-17 and TNFα and the regulatory cytokines IL-10, and IL-31, since cytokines may also have a direct effect on the brain such as fatigue and appetite. GD patients have increased levels of proinflammatory cytokines in serum. In addition, recent research defines new biomarkers indicating organic structural nerve damage – neurofilament - indicating damage to long axons, and gliofibrillar acid protein (GFAP) in astrocytes indicating brain damage and inflammation. These biomarkers are collectively referred to as autoimmune biomarkers in this applicationSTRONG·

MFS is a well validated scale to capture the mental fatigue (17). It consists of 15 questions and is invariant to age, gender, and education. ThyPro is a thyroid specific QoL self-assessment questionnaire (18). It measures QoL with 13 scales, covering physical and mental symptoms, as well as the impact of thyroid disease on social and daily life.

Time plan and Implementation: SU has 150-200 referrals for GD per year. Patients are enrolled at the Thyroid Unit by me and my supervisor. The data collection can start in Q3 2019 after project registration and ethical approval with patient inclusion completed in Q1 2021. Last patient visit is scheduled Q2 2022. Biomarker analysis will be in 2022.

Organisation: GPCRs, VGKC, NMDAR, GAD, IGF-I, thyroglobulin, TPOab, and cytokines will be done at Dept of Clinical Immunology, SU by immunologists Doc A Lundgren and Doc C Malmeström. Dept of Biochemistry, SU, has established serum methods for neurofilament and GFAP.

Risk analysis and contingency planning: We may have chosen the wrong autoimmune biomarkers and there is a risk that WP1 may prove negative. This is an explorative study in an unexplored field. It is reasonable to take a risk to gain new knowledge. If WP1 should yield negative results, we still expect WP2 to produce valuable results.

Metod: Databearbetning

Statistics is drafted by Statistiska Konsultgruppen, Göteborg.

The brain-derived biomarkers at baseline, the routine endocrine data and the patients’ background data will all be investigated with univariable logistic regression analyses for their power for univariable prediction of persistent mental fatigue at the 15 months follow-up. Clinical relevant variables with univariable p-value <0.10 will then be entered in a stepwise multivariable logistic regression in order to find significant independent predictors to mental fatigue. The correlations between the variables and between their values at baseline and 15 months will also be analysed to find possible causal connections. Other significant independent predictors, interactions between predictors and non-linear relations will also be investigated.

Förväntat resultat / Betydelse / Originalitet

Our research introduces a new concept in GD. To our knowledge, there are no other studies investigating if persistent mental fatigue is caused by autoimmunity; however, it is line with several findings in the new research field of immunopsychiatry (19). All earlier studies on structural brain changes and hyperthyroidism are cross-sectional. We lack an understanding whether the structural changes in hyperthyroidism from GD are reversed by regaining euthyroidism, whether they are correlated with the level of cognitive functioning, whether the patients’ psychiatric diagnoses influence outcome and whether biological markers can predict who will and who will not recover from cognitive symptoms. The proposed research attempts to fill these knowledge gaps.

In WP 1, this project will for the first time systematically identify brain related autoimmune biomarkers and put them into a clinical context of GD patients,

If our hypothesis is proven, and this project is successfully conducted, we will identify clinically relevant biomarkers that predict cognitive deterioration in GD. Such information would set the stage for future interventional studies.

As mental fatigue is hard to treat, it is important for the patient to adapt to living with the condition. Knowledge is important for health service, as many of these patients often feel neglected. Effective biomarkers would enable us to identify patients in need of extra support – evidenced-based methods motivate new investments into laboratory assays and imaging methods. But most importantly, this research may lead to new knowledge that provides input for new treatment and prevention strategies within the underexplored field of GD and the brain. In addition, it may lead to novel approaches for managing patients with similar mental symptoms, but without any known autoimmune disease.

Referenser (max 20 stycken)

1. Abraham-Nordling M, Bystrom K, Torring O, Lantz M, Berg G, Calissendorff J, Filipsson Nystrom H, Jansson S, Jorneskog G, Karlsson A, Nystrom E, Ohrling H, Orn T, Hallengren B, Wallin G. Incidence of Hyperthyroidism in Sweden. Eur J EndocrinolEM 2011;

2. Li L, Zhi M, Hou Z, Zhang Y, Yue Y, Yuan Y. Abnormal brain functional connectivity leads to impaired mood and cognition in hyperthyroidism: a resting-state functional MRI study. OncotargetEM 2017; 8:6283-6294

3. Brandt F, Thvilum M, Almind D, Christensen K, Green A, Hegedus L, Brix TH. Hyperthyroidism and psychiatric morbidity: evidence from a Danish nationwide register study. Eur J EndocrinolEM 2014; 170:341-348

4. Elberling TV, Rasmussen AK, Feldt-Rasmussen U, Hording M, Perrild H, Waldemar G. Impaired health-related quality of life in Graves' disease. A prospective study. Eur J EndocrinolEM 2004; 151:549-555

5. Torring O, Tallstedt L, Wallin G, Lundell G, Ljunggren JG, Taube A, Saaf M, Hamberger B. Graves' hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. Thyroid Study Group. J Clin Endocrinol MetabEM 1996; 81:2986-2993

6. Perrild H, Hansen JM, Arnung K, Olsen PZ, Danielsen U. Intellectual impairment after hyperthyroidism. Acta Endocrinol (Copenh)EM 1986; 112:185-191

7. Bunevicius R, Prange AJ, Jr. Thyroid disease and mental disorders: cause and effect or only comorbidity? Curr Opin PsychiatryEM 2010; 23:363-368

8. Zhang W, Song L, Yin X, Zhang J, Liu C, Wang J, Zhou D, Chen B, Lii H. Grey matter abnormalities in untreated hyperthyroidism: a voxel-based morphometry study using the DARTEL approach. Eur J RadiolEM 2014; 83:e43-48

9. Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway. J ImmunolEM 2003; 170:6348-6354

10. Xu J, Zhao L, Xiang G, Xu C. Relationship between autoantibody to the angiotensin II-1 receptor and cardiovascular manifestations of Graves' disease. Exp Clin Endocrinol DiabetesEM 2014; 122:254-258

11. Stavrakis S, Yu X, Patterson E, Huang S, Hamlett SR, Chalmers L, Pappy R, Cunningham MW, Morshed SA, Davies TF, Lazzara R, Kem DC. Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism. Journal of the American College of CardiologyEM 2009; 54:1309-1316

12. Saavedra JM, Sanchez-Lemus E, Benicky J. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications. PsychoneuroendocrinologyEM 2011; 36:1-18

13. Mader S, Brimberg L, Diamond B. The Role of Brain-Reactive Autoantibodies in Brain Pathology and Cognitive Impairment. Front ImmunolEM 2017; 8:1101

14. Nataf S. Evolution, immunity and the emergence of brain superautoantigens. F1000ResEM 2017; 6:171

15. Takagi M, Ishigaki Y, Uno K, Sawada S, Imai J, Kaneko K, Hasegawa Y, Yamada T, Tokita A, Iseki K, Kanno S, Nishio Y, Katagiri H, Mori E. Cognitive dysfunction associated with anti-glutamic acid decarboxylase autoimmunity: a case-control study. BMC NeurolEM 2013; 13:76

16. Pohlmann A, Karczewski P, Ku MC, Dieringer B, Waiczies H, Wisbrun N, Kox S, Palatnik I, Reimann HM, Eichhorn C, Waiczies S, Hempel P, Lemke B, Niendorf T, Bimmler M. Cerebral blood volume estimation by ferumoxytol-enhanced steady-state MRI at 9.4 T reveals microvascular impact of alpha1 -adrenergic receptor antibodies. NMR BiomedEM 2014; 27:1085-1093

17. Johansson B, Starmark A, Berglund P, Rödholm M, Rönnbäck L. A self-assessment questionnaire for mental fatigue and related symptoms after neurological disorders and injuries. Brain InjuryEM 2010; 24:2-12

18. Watt T, Hegedus L, Groenvold M, Bjorner JB, Rasmussen AK, Bonnema SJ, Feldt-Rasmussen U. Validity and reliability of the novel thyroid-specific quality of life questionnaire, ThyPRO. Eur J EndocrinolEM 2010; 162:161-167

19. Pariante CM. Psychoneuroimmunology or immunopsychiatry? Lancet PsychiatryEM 2015; 2:197-199


Den autoimmuna hjärnan- ett nytt koncept vid Graves sjukdom, from FoU i Västra Götalandsregionen
http://au.researchweb.org/is/vgr/project/260071