Exploring Immunological Markers Associated With Mental Fatigue in Graves' Disease

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

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.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Diseases; Thyroid Diseases; Mental Fatigue; Graves Ophthalmopathy; Graves Disease

• Study Type: Observational
• Enrollment (Estimated): 180

Contacts and Locations

• Study Contact: Name: Karin Tammelin; Phone Number: +46313427331; Email: karin.tammelin@vgregion.se

Study Locations

• Sweden
  • Gothenburg, Sweden, 41346
    • Recruiting
    • Department of Endocrinology, Sahlgrenska University Hospital
    • Contact: Karin Tammelin, MD; Phone Number: 0313427331; Email: karin.tammelin@vgregion.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 72 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients are recruited from the both previous patients at the Endocrine outpatient Clinic at Sahlgrenska University Hospital in Gothenburg and from advertising. They are invited to a web based screening form where the ones eligible are contacted by study personal and eligibility criteria are checked again.

Controls are recruited by the same way and by contacting a random sample from the population registration (based on Swedish social security number).

Groups are matched for age, educational level and smoking habits.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Graves' patients with mental fatigue; 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; 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; Women without current or previous thyroid disease and with Mental Fatigue Scale scores of less than 8

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region
• Investigators: Principal Investigator: Helena Filipsson, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Estimated): December 20, 2028
• Study Completion (Estimated): December 20, 2028

Study Registration Dates

• First Submitted: December 19, 2022
• First Submitted That Met QC Criteria: January 4, 2023
• First Posted (Actual): January 10, 2023

Study Record Updates

• Last Update Posted (Estimated): September 29, 2025
• Last Update Submitted That Met QC Criteria: September 23, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Biomarkers; Cerebrospinal fluid in Graves' disease
• Additional Relevant MeSH Terms: Endocrine System Diseases; Genetic Diseases, Inborn; Immune System Diseases; Behavioral Symptoms; Eye Diseases; Eye Diseases, Hereditary; Exophthalmos; Orbital Diseases; Goiter; Hyperthyroidism; Fatigue; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Thyroid Diseases; Graves Ophthalmopathy; Autoimmune Diseases; Graves Disease; Mental Fatigue
• Other Study ID Numbers: ImmunoGraves WP1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No