Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Nemat-Gorgani, Mohsen, Jensen, Michael Anthony, Davis, Ronald Wayne · International journal of molecular sciences · 2025 · DOI
Quick Summary
Your brain has a cleaning system called the glymphatic system that removes toxic waste buildup, especially during sleep. This review suggests that this cleaning system may not be working properly in ME/CFS, which could explain symptoms like fatigue and brain fog. If the glymphatic system is involved in ME/CFS, new treatments designed to fix this cleaning process might help patients feel better.
Why It Matters
ME/CFS lacks established biomarkers and effective treatments, with 90% of patients remaining undiagnosed. Identifying the glymphatic system as a potential contributor opens a new avenue for understanding disease mechanisms and developing targeted therapeutics that could meaningfully improve patient outcomes.
Observed Findings
The glymphatic system's role in removing toxic metabolic wastes during sleep is established in general neuroscience literature
Glymphatic dysfunction has been documented in other neurological disorders including Alzheimer's disease
ME/CFS symptoms (fatigue, brain fog, sleep dysfunction, post-exertional malaise) are consistent with impaired metabolic waste clearance
An estimated 90% of ME/CFS patients remain undiagnosed despite decades of research
No effective medical treatments or simple diagnostics currently exist for ME/CFS
Inferred Conclusions
Glymphatic dysfunction may be an important contributor to ME/CFS pathophysiology
Therapeutics that modulate glymphatic function warrant investigation as potential ME/CFS treatments
The glymphatic system deserves serious consideration by the ME/CFS medical and scientific community as a research focus
Understanding glymphatic mechanisms could lead to improved diagnostic and treatment approaches
Remaining Questions
Do ME/CFS patients actually show glymphatic system dysfunction on objective neuroimaging or biochemical testing?
What This Study Does Not Prove
This review does not provide experimental evidence that glymphatic dysfunction actually occurs in ME/CFS patients—it proposes a hypothesis based on theoretical reasoning and research in other diseases. The study does not demonstrate causation or prove that treating glymphatic dysfunction would effectively treat ME/CFS. Direct neuroimaging and biochemical studies in ME/CFS populations would be needed to establish this mechanism.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
Which specific aspects of glymphatic function (aquaporin-4 expression, cerebrospinal fluid dynamics, waste clearance efficiency) are altered in ME/CFS?
What causes glymphatic dysfunction in ME/CFS—viral infection, autonomic dysfunction, mitochondrial dysfunction, or other mechanisms?
Would therapies targeting glymphatic function (sleep optimization, pharmacological agents, physical interventions) effectively treat ME/CFS symptoms in clinical trials?