Tag: glymphatic system

The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of SARS-CoV-2 infection (Long COVID) are complex multisystem disorders affecting 60–400 million individuals globally. They are considered post-infectious illnesses and share similar biological mechanisms, including immune dysregulation, orthostatic intolerance and cognitive dysfunction, highlighting a substantial overlap between the two conditions. Persistent fatigue, sleep dysfunction, post-exertional malaise and brain fog are among some of their most common and debilitating symptoms.
Despite extensive research, they remain incurable, with no effective treatments, or simple diagnostic tests. They are increasingly understood as heterogeneous, multisystem diseases, involving neurological symptoms, with varying severities and diverse underlying biological abnormalities. More recently, the possibility of glymphatic dysfunction and autophagy impairment have been proposed as parts of the mechanistic features of the pathophysiology of these conditions, which are discussed more fully in the present perspective.
With the glymphatic and meningeal lymphatic systems being operationally integrated, we will try to delineate how the metabolic waste removal mechanism afforded by this system may work together with autophagy to maintain brain homeostasis. We will provide some of the established mechanistic features of toxicity of misfolded proteins, explore their role in causing glymphatic dysfunction and impairing autophagy, and discuss the potential for therapeutic interventions.
Source: Nemat-Gorgani M, Jensen MA, Davis RW. The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective. International Journal of Molecular Sciences. 2026; 27(20):9351. https://doi.org/10.3390/ijms27209351 https://www.mdpi.com/1422-0067/27/20/9351 (Full text)

Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

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.

Source: Nemat-Gorgani M, Jensen MA, Davis RW. Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Nov 27;26(23):11524. doi: 10.3390/ijms262311524. PMID: 41373677. https://www.mdpi.com/1422-0067/26/23/11524 (Full text)

Retinal nerve fiber layer thinning in chronic fatigue syndrome as a possible ocular biomarker of underlying glymphatic system dysfunction

In a recent article published in Medical Hypotheses, my colleague and I speculated that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome (CFS) [1]. We further postulated that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain. In this context, it would be helpful to have a predictive biomarker that can identify CFS patients who are good candidates for this specific treatment. For reasons discussed below, I believe that retinal nerve fiber layer (RNFL) thinning may be a sign of underlying glymphatic system dysfunction in neurodegenerative diseases that result from protein toxicity.

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