Epigenetics of Post-exertional Malaise in Patients With ME/CFS

Fatigue Syndrome, Chronic Clinical Trial

— EPIME  

Official title:

The Influence of Epigenetic Modifications and Post-Exertional Malaise in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04378634
• Other study ID #: EPIME
• Status: Completed
• Phase: N/A
• Start date: April 1, 2021
• Est. completion date: April 30, 2023

Study information

• Verified date: November 2023
• Source: Vrije Universiteit Brussel
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Exploring epigenetic mechanisms of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is crucial to understand the mechanisms underlying its pathophysiology. Three potential candidates have been selected (BDNF, COMT, and HDAC genes). DNA methylation in the promoter regions of those genes will be explored. The investigators designed a randomised controlled trial and will enrol 70 patients with ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups and receive either one session of aerobic exercise or a validated test designed to trigger mental stress and mental fatigue. The primary aim is to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes in response to exercise and the stress task.

Description:

The only way to improve the diagnosis and treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is to better understand the mechanisms underlying its pathophysiology. Central nervous system dysfunctions play a major role in ME/CFS and help explaining patients' symptoms, such as general malaise occurring after physical activity (i.e. post-exertional malaise). Therefore, post-exertional malaise in relation to three major candidates involved in central nervous system functioning - brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT) and histone de-acetylases (HDAC) - will be explored. BDNF is a protein involved in crucial functions such as nerve growth, memory and learning, and plays a role in neuronal sensitisation and pain. However, no study has explored the role of BDNF in ME/CFS. Our research group performed a preliminary study which focussed on BDNF in ME/CFS. In a previous study, the investigators assessed DNA methylation (an epigenetic mechanism that contribute to gene expression silencing), and protein expression in serum of the BDNF in patients with ME/CFS and healthy controls. Patients showed significantly less DNA methylation and significantly more BDNF protein. Given these exciting findings, further study is warranted. COMT is an enzyme encoded by its homonymous gene. The enzyme degrades catecholamines like dopamine, epinephrine and norepinephrine. Catecholamines have been repeatedly associated with pain, stress, and depression. Lower COMT activity increases catecholamines level, causes hyperalgesia, and has been associated with depressive symptoms. Similarly, research on histone acetylation shows that another group of enzymes (Histone de-acetylases, HDACs) are increased during neural sensitisation and pain. However, no research has been done on HDACs in patients with ME/CFS. Interestingly, aerobic exercise has been shown to increase BDNF release and decrease COMT and HDACs activity. Given the detrimental acute effects that exercise can have on patients with ME/CFS, investigators hypothesised that understanding the role of BDNF, COMT, and HDACs following exercise would help elucidating both mechanisms of post-exertional malaise and ME/CFS pathophysiology. A randomised controlled trial has been designed including 70 patients with ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups. One group will undergo one session of aerobic exercise, and the other group undergoes a validated test designed to trigger mental stress and mental fatigue. All participants will undergo clinical assessments, measurements of pain thresholds, and blood withdrawal before and after the exercise/mental stress exposure. The aims are to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes, as well as the expression of these factors in blood and serum in patients with ME/CFS.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 105
• Est. completion date: April 30, 2023
• Est. primary completion date: April 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• diagnosis of ME/CFS established by a MD experienced in the field of internal medicine and ME/CFS - according to the published international criteria developed by the Canadian Consensus Criteria (CCC);
• age between 18 and 70 years old;
• body mass index (BMI) below 30 (no obesity).

Exclusion Criteria:

• presence of other neurological disorders (Parkinson's disease, Multiple Sclerosis, etc);
• presence of systemic disorders (lupus erythematosus, rheumatoid arthritis, etc.);
• presence or history of cardiac disorders (coronary heart disease, history of heart failure, etc);
• presence or history of cancer;
• presence or history of neuropathic pain (e.g. pain related to herpes zoster virus);
• pregnancy;

Related Conditions & MeSH terms

• Fatigue
• Fatigue Syndrome, Chronic
• Syndrome

Intervention

Behavioral:
• Exercise
Sub-maximal exercise test

Other:
• Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks

Locations

Country	Name	City	State
Belgium	UZ Brussel	Brussels

Sponsors (1)

Lead Sponsor	Collaborator
Vrije Universiteit Brussel

Country where clinical trial is conducted

Belgium, 

References & Publications (3)

de Vega WC, Vernon SD, McGowan PO. DNA methylation modifications associated with chronic fatigue syndrome. PLoS One. 2014 Aug 11;9(8):e104757. doi: 10.1371/journal.pone.0104757. eCollection 2014. — View Citation

Trivedi MS, Oltra E, Sarria L, Rose N, Beljanski V, Fletcher MA, Klimas NG, Nathanson L. Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns. PLoS One. 2018 Jul 23;13(7):e0201066. doi: 10.1371/journal.pone.0201066. eCollection 2018. — View Citation

Vangeel EB, Kempke S, Bakusic J, Godderis L, Luyten P, Van Heddegem L, Compernolle V, Persoons P, Lambrechts D, Izzi B, Freson K, Claes S. Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients. J Psychosom Res. 2018 Jan;104:55-60. doi: 10.1016/j.jpsychores.2017.11.011. Epub 2017 Nov 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	General Health	General health will be measured using the Short Form-36 Health Survey (SF-36) questionnaire. The questionnaire returns a score from 0 to 100 where higher scores mean less disability.	Baseline
Other	Gene's polymorphisms	Genes' polymorphisms might mediate epigenetic changes. They will be assessed using pyrosequencing technology.	Baseline
Primary	DNA methylation	DNA methylation measured at several CpGs of the genes' promoter regions using pyrosequencing technology	Baseline through 1 week post intervention
Secondary	Clinical Symptoms	Symptoms reported by the patients using the DePaul Symptoms Questionniare	Baseline through 1 week post intervention
Secondary	Pain sensitivity	Sensitivity to mechanical stimuli using a digital algometer (FPXTM, Fisher, Wagner Instruments, Greenwich) as well as heat and cold stimuli using the TSA-II device (Medoc, CA, USA). The devices will be placed, in random order to prevent test order effects, at three different body sites: the skin web between thumb and index finger, trapezius muscle, and proximal third of tibialis anterior muscle, in order to test pain thresholds on non-specific locations both on the extremities and the trunk.	Baseline through 1 week post intervention
Secondary	Serum BDNF	BDNF protein expression in serum using Enzyme-Linked Immunosorbent Assay (ELISA) kit for human BDNF	Baseline through 1 week post intervention
Secondary	Cortisol response	Cortisol will be measured in saliva and used as a measure of stress responses using LC/MS-MS method.	Baseline through 1 week post intervention