Hypothesis Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2025, Nemat-Gorgani et al

[John Mac]

Abstract​

Defined by the World Health Organization as a neurological disorder, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness, affecting millions of people worldwide. First reported in the early nineteenth century, ME/CFS is uniquely characterized by a wide array of symptoms, including fatigue, brain fog, post-exertional malaise (PEM), sleep dysfunction, and orthostatic intolerance (OI).

Despite decades of extensive research, there are no effective medical treatments or simple diagnostics for ME/CFS, with an estimated 90% of patients remaining undiagnosed.

The recently discovered glymphatic system, a lymphatic analog of the brain, is believed to be responsible for the removal of toxic metabolic wastes accumulated in the course of daily activities, primarily during sleep. A link between glymphatic dysfunction and some neurological disorders such as Alzheimer’s disease has already been established, raising the possibility of its involvement in ME/CFS.

Accordingly, we believe the ME/CFS medical/scientific community will be interested in seriously considering GD an important contributor to its pathophysiology. If so, therapeutics that modulate glymphatic function may also benefit patients with ME/CFS.

https://www.mdpi.com/1422-0067/26/23/11524#:~:text=Defined%20by%20the%20World%20Health,affecting%20millions%20of%20people%20worldwide.

 

[leokitten]

So yet another theory paper without any data...

 

[Trish]

I have no idea whether the hypothesis makes sense, but I can't help wondering, if glymphatic dysfunction is a causal factor in ME/CFS, why haven't lots of us who have had ME/CFS for decades also developed Alzheimers?

 

[EndME]

I have no idea whether the hypothesis makes sense, but I can't help wondering, if glymphatic dysfunction is a causal factor in ME/CFS, why haven't lots of us who have had ME/CFS for decades also developed Alzheimers?

From what I understand glympathic dysfunction as cause of Alzheimers is merely a hypothesis for Alzheimers and as pretty much anything else in the field contested. I once read an article on the topic which made it seem like it was people fighting for political prominence with work that had not been yet shown to be of relevance in humans: https://www.nature.com/articles/d41586-025-00962-y#ref-CR1.

I suspect once something new is discovered, people write papers about it whether it is of relevance or not, in particular in fields where there have been no breakthroughs for decades but where a much celebrated career awaits those that do so.

 

[DMissa]

I expected perrin when I saw the topic

 

[Jonathan Edwards]

The recently discovered glymphatic system, a lymphatic analog of the brain, is believed to be responsible for the removal of toxic metabolic wastes accumulated in the course of daily activities, primarily during sleep.

Believed by whom, I wonder? Certainly not by me. Metabolic waste must be removed by venules, otherwise the brain would stop working within minutes. The glymphatics would take hours.

 

[SNT Gatchaman]

That's assuming that in the brain metabolic by-products are waste and that all are needed to be cleared rapidly. Lactate in particular might be a signalling molecule that the brain needs and a universal fuel.

See Glymphatic clearance controls state-dependent changes in brain lactate concentration (2017)

 

[DMissa]

That's assuming that in the brain metabolic by-products are waste and that all are needed to be cleared rapidly.

There is a tendency for things in biology to be labelled “good” and “bad” when it almost never ends up being so simple. “Never too much of a good thing” underpins the entire supplements industry though… sigh

 

[Sean]

Life Tips

1) It's never that simple.

 

[Sly Saint]

Brain Waste-Clearance Impairments Tied to ME/CFS​

A new perspective article from Stanford researchers proposes that dysfunction of the glymphatic system, the brain’s waste-clearance network, may be a central contributor to the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The glymphatic system typically removes metabolic byproducts such as lactate, glutamate, tau, and beta-amyloid, especially during deep sleep.

When this system is impaired, these metabolites can accumulate, triggering oxidative stress, neuroinflammation, and impaired neuronal signaling.​

The authors outline multiple biological pathways in ME/CFS that may converge on glymphatic failure, including blood–brain barrier disruption, chronic neuroinflammation, mitochondrial dysfunction, impaired cerebral blood flow, sleep instability, dysautonomia, and viral reactivation. They highlight AQP4, a water-channel protein in astrocytes essential for glymphatic flow, as a possible mechanistic link: oxidative stress, autoantibody activity, or membrane disruption may mislocalize or reduce AQP4, compromising waste clearance.

These disruptions may help explain hallmark symptoms such as post-exertional malaise, brain fog, unrefreshing sleep, and orthostatic intolerance.​

The paper also discusses emerging therapeutic strategies targeting glymphatic function, including sleep-based interventions, neuromodulation, and agents that modulate AQP4 regulation.

While not a clinical study, the article provides a cohesive model that unifies many ME/CFS abnormalities within a glymphatic-centered framework, offering new directions for diagnostics and future treatment research. The findings add to a growing body of evidence confirming that the cognitive and neurological challenges described by ME/CFS patients are rooted in identifiable biological dysfunction, directly countering the long-held misconception that these symptoms were imagined.

Brain Waste-Clearance Impairments Tied to ME/CFS

Findings show brain waste-clearance dysfunction in ME/CFS, providing biological evidence that validates symptoms patients were once told were “in their head.”

www.autoimmuneinstitute.org

 

[ME/CFS Science Blog]

The paper writes:

AQP4 water channels are the primary pathway for water movement into the brain’s interstitial space, and when dysfunctional, this process is significantly reduced. AQP4proteins are expressed at the plasma membrane of astrocytes throughout the central nervous system and are essential to the functioning of the glymphatic system. They facilitate the exchange of fluids between CSF and ISF.

We also hypothesize that anti-AQP4 autoantibodies may be involved in the pathophysiology of ME/CFS as a neuroimmune disorder.

But on X someone commented:

"There is already a known autoimmune disease of the CNS, where autoantibodies directed against AQP4 its named Neuro Myelitis Optica (NMO) The autoantibodies were discovered in 2006/07."​

​

"The AQP4 autoantibodies causes extensive and severe inflammation and demyelination and if patients are left untreated with immunosuppressants 50% will be blind or tetraplegic within 5 years. So I doubt AQP4 ab is the main issue in ME."​

​

More info here:

Anti-AQP4 disease - Wikipedia

en.wikipedia.org