Epigenetics of Post-exertional Malaise in Patients With ME/CFS
Kľúčové slová
Abstrakt
Popis
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 with cross-over has been designed including 80 patients with ME/CFS and 25 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.
Termíny
| Naposledy overené: | 04/30/2020 |
| Prvý príspevok: | 04/26/2020 |
| Odhadovaná registrácia bola odoslaná: | 05/04/2020 |
| Prvý príspevok: | 05/06/2020 |
| Posledná aktualizácia bola odoslaná: | 05/04/2020 |
| Posledná aktualizácia bola zverejnená: | 05/06/2020 |
| Aktuálny dátum začatia štúdie: | 09/30/2020 |
| Odhadovaný dátum dokončenia primárneho okruhu: | 09/29/2021 |
| Odhadovaný dátum dokončenia štúdie: | 09/29/2022 |
Stav alebo choroba
Intervencia / liečba
Behavioral: Exercise
Other: Mental Stress Test
Fáza
Skupiny zbraní
| Arm | Intervencia / liečba |
|---|---|
| Experimental: ME/CFS Exercise Patients undergoing exercise first and the mental stress task after wash-out | |
| Experimental: Patients Stress Patients undergoing the mental stress task first and exercise after wash-out | |
| Active Comparator: Healthy Exercise Healthy controls undergoing exercise first and the mental stress task after wash-out | |
| Active Comparator: Healthy Stress Healthy controls undergoing the mental stress task first and exercise after wash-out |
Kritériá oprávnenosti
| Vek vhodný na štúdium | 18 Years To 18 Years |
| Pohlavia vhodné na štúdium | Female |
| Prijíma zdravých dobrovoľníkov | Áno |
| Kritériá | 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 Centre for Disease Control and Prevention (CDC); - 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; |
Výsledok
Primárne výstupné opatrenia
1. DNA methylation [Baseline through 1 week post intervention]
Opatrenia sekundárnych výsledkov
1. Clinical Symptoms [Baseline (pre-intervention), immediately post-intervention, at 24-hours, at 1-week]
2. Pain sensitivity [Baseline (pre-intervention), immediately post-intervention, at 24-hours, at 1-week]
3. Serum BDNF [Baseline (pre-intervention), immediately post-intervention, at 24-hours, at 1-week]
4. Salivary Cortisol [Baseline (pre-intervention), immediately post-intervention, at 24-hours, at 1-week]
Ostatné výstupné opatrenia
1. General Health [Baseline]
2. Gene's polymorphisms [Baseline]
