Exploring Immunological Markers Associated With Mental Fatigue in Graves' Disease

Study Overview
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Brief Summary
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Mental fatigue occurs in many diseases and the reasons are mostly unknown. The investigators hypothesize that remaining mental fatigue after restored hyperthyroidism in Graves' disease is an autoimmune complication. The aim of this study is to explore immunological markers possibly associated with mental fatigue in Graves' disease, which the investigators plan to validate in another study (ImmunoGraves wp 2). Using a cross-sectional study design, mental fatigue is scored using a questionnaire to find 60 patients with and 60 without mental fatigue 15-60 months after diagnosis of Graves disease. The patients and 60 thyroid healthy controls without mental fatigue are assessed for thyroid hormones, quality of life, anxiety and depression, self-evaluated stress, coping strategies, eye symptoms and background variables. SciLifeLab in Stockholm, the national facility for autoimmune profiling, has pre-set large arrays including 42000 human proteins. Serum and cerebrospinal fluid will be separately pooled and analysed for a subgroup of patients with or without mental fatigue and for a subgroup of the control group. Proteins that preferably bind to antibodies in sera and/or cerebrospinal fluid from Graves' patients with mental fatigue in comparison to non-mental fatigue patients, will be screened against the Human Protein Atlas and the Allen brain map to identify those proteins that are expressed in the brain. Antibodies at higher concentration in the mental fatigue pools compared to the group without mental fatigue will be selected for further analyses on an individual level in the whole cohort together with antibodies targeting g-protein coupled receptors, thyroid autoantibodies, cytokines and biomarkers indicating organic and structural nerve damage.

Official Title
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Exploring Immunological Markers in Blood and Cerebrospinal Fluid Associated With Mental Fatigue in Euthyroidism After Graves' Disease- a Cross Sectional Study

Conditions
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Graves Disease, Graves Ophthalmopathy, Mental Fatigue, Autoimmune Diseases, Thyroid Diseases

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria If patient: Graves' disease with positive TSH-receptor antibodies and thyroid hormones above the upper reference limit at diagnosis Diagnosis15 to 60 months ago. If recidive both episodes must have occurred within 15 months to 60 months. Thyroid hormones within normal range without anti thyroid drugs If control: No thyroid disease Patient and control without mental fatigue: Mental Fatigue Score ≤8 (cut off 10.5) Patient with mental fatigue: Mental Fatigue Score >13 and debut of symptoms of mental fatigue in parallel with debut of Graves' disease, without other obvious cause Exclusion Criteria Person unable to follow protocol Multiple sclerosis, myalgic encephalomyelitis/chronic fatigue syndrome, any other neurological disease Traumatic brain injury with unconsciousness Other disease strongly associated with fatigue Pregnancy and breast-feeding On-going or recent systemic treatment with steroids Radioiodine therapy within the last 18 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 72 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Graves' patients with mental fatigue<br>Women diagnosed with Graves 15 moths to 60 months ago with Mental Fatigue Scale score of more than 13 (maximum 42, cut of 10,5 for mental fatigue) | |
| Graves' patients without mental fatigue<br>Women diagnosed with Graves 15 moths to 60 months ago with Mental Fatigue Scale score of less than 8 (maximum 42, cut of 10,5 for mental fatigue) | |
| Thyroid healthy controls without mental fatigue<br>Women without current or previous thyroid disease and with Mental Fatigue Scale scores of less than 8 | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identifying autoantibodies targeting antigens occurring in the brain that are higher in Graves' disease complicated by mental fatigue than in Graves' disease not complicated by mental fatigue | Each group will be analysed in arrays for antibodies targeting 42000 human proteins (ScilifeLabs, Stockholm). Proteins binding to antibodies in mental fatigue patients will be screened against the Human Protein Atlas (www.proteinatlas.org) and the Allen brain map (www.brain-map.org) and those expressed in the brain will be compared between groups. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identifying autoantibodies targeting antigens occurring in the brain that are higher in Graves' disease complicated by mental fatigue than in thyroid healthy controls without mental fatigue | Each group will be analysed in arrays for antibodies targeting 42000 human proteins (ScilifeLabs, Stockholm). Proteins binding to antibodies in mental fatigue patients will be screened against the Human Protein Atlas (www.proteinatlas.org) and the Allen brain map (www.brain-map.org) and those expressed in the brain will be compared between groups. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Identifying autoantibodies targeting antigens occurring in the brain that are higher in Graves' disease not complicated by mental fatigue than in thyroid healthy controls without mental fatigue | Each group will be analysed in arrays for Ab targeting 42000 human proteins (ScilifeLabs, Stockholm). Proteins binding to Ab in MF patients will be screened against the Human Protein Atlas (www.proteinatlas.org) and the Allen brain map (www.brain-map.org) and those expressed in the brain will be compared between groups. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Thyroid autoantibodies compared between Graves' disease complicated by mental fatigue, Graves' disease not complicated by mental fatigue and healthy controls | Levels of thyroid autoantibodies will be analysed with the standard method of the laboratory at Sahlgrenska University Hospital. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Cytokines compared between Graves' disease complicated by mental fatigue, Graves' disease not complicated by mental fatigue and healthy controls | Levels of cytokines will be analysed with the standard method of the laboratory at Sahlgrenska University Hospital. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Biomarkers indicating organic and structural nerve damage compared between Graves' disease complicated by mental fatigue, Graves' disease not complicated by mental fatigue and healthy controls | Biomarkers will be analysed with the standard method of the laboratory at Sahlgrenska University Hospital. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Autoantibodies to other g-protein coupled receptors compared between Graves' disease complicated by mental fatigue, Graves' disease not complicated by mental fatigue and healthy controls | Levels of autoantibodies to g-protein coupled receptors will be measured using enzyme-linked immunosorbent assays | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Prevalence of endocrine ophthalmopathy in Graves' complicated by mental fatigue compared to prevalence of endocrine ophtalmopathy in Graves' not complicated by mental fatigue | Prevalence defined as endocrine ophthalmopathy that has required assessment/and or follow up at ophthalmologist. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Self evaluated quality of life in relation to ophthalmopathy will be compared between patients with Graves' with and without mental fatigue and to healthy controls | Evaluated by the validated questionnaire the Graves' Ophthalmopathy Quality of Life Questionnaire (GO QoL). | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Self evaluated quality of life in relation to thyroid symptoms will be compared between patients with Graves' with and without mental fatigue and to healthy controls | Evaluated by the validated questionnaire Thyroid-specific Patient-Reported Outcome short-form (ThyPro 39) | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Self evaluated quality of life and well being will be compared between patients with Graves' with and without mental fatigue and to healthy controls | Evaluated by the validated questionnaire Psychological General Well Being index (PGWB) | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Self evaluated symptoms of anxiety and depression will be compared between patients with Graves' with and without mental fatigue and to healthy controls | Evaluated by the validated questionnaire the Comprehensive Psychopathological Rating Scale (CPRS). | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Self evaluated stress will be compared between patients with Graves' with and without mental fatigue and to healthy controls | Evaluated by the validated questionnaire Perceived Stress Scale (PSS-14). | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Coping strategies will be compared between patients with Graves' with and without mental fatigue and to healthy controls | Evaluated by the validated questionnaire Brief cope. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Optimistic self-beliefs to cope with difficulties in life will be compared between patients with Graves' with and without mental fatigue and to healthy controls | Evaluated by the validated questionnaire General self efficacy. | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 
| Personality traits will be compared between patients with Graves' with and without mental fatigue and to healthy controls | Evaluated by the validated questionnaire NEO Five-Factor Inventory-3 (NEO-FFI-3). | Patients and controls will be examined at one occasion, for patients 15-60 months after diagnosis of Graves' disease. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biomarkers, Cerebrospinal fluid in Graves' disease