"The brain’s waste clearance system is impaired in people living with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) which can lead to various symptoms including brain fog, Griffith University researchers have discovered

Brain’s waste-clearing ability impaired in ME/CFS patients

Credit: Griffith University

The brain’s waste clearance system is impaired in people living with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) which can lead to various symptoms including brain fog, Griffith University researchers have discovered.

The research demonstrates, for the first time, the impact ME/CFS has on glymphatic function which is responsible for clearing the brain of metabolic waste products and is mostly active during sleep and disengaged while a person is awake.

Lead author Dr Kiran Thapaliya from Griffith’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) said when the brain’s waste clearance system did not work properly, harmful waste could build up causing neuroinflammation.

“This study is the first to demonstrate impaired glymphatic function in ME/CFS using MRI, providing a mechanistic explanation for the inflammatory changes reported by other Australian and international teams,” he said.

“This suggests that dysfunction in the brain’s natural cleaning system may be a key driver of this condition.”

Professor Sonya Marshall-Gradisnik, NCNED Director, said not only did reduced glymphatic function cause brain fog, but also caused sleep disturbance.

“The study found worse sleep is associated with poor brain waste clearance, reinforcing the notion that sleep plays a critical role in maintaining brain health,” she said.

“We hope the results can pave the way for better diagnosis through the use of non-invasive procedures, and importantly, future treatment for patients.”

The paper ‘Disrupted glymphatic function and its relationship with sleep and cognitive impairment in ME/CFS assessed via DTI-ALPS’ has been published in Frontiers in Neuroscience."

link to article

We have published a preprint titled “Evolutionary shifts in spike glycan-binding specificity suggest a possible association with host adaptation during SARS-CoV-2 Omicron evolution” .

Neuroimaging study hailing from Amsterdam

TLDR: The authors propose:

First - brain inflammation tracks with weaker connectivity in the visual and attention networks - and between the brainstem and a control network.

Second - the complaints (fatigue, brain fog) track with weaker connectivity in the default mode network (the network active when your mind wanders, reflects, remembers) - and between the thalamus and motor cortex.

Explainer Thread:

https://threadreaderapp.com/thread/2072299711265194404.html

"In this integrative review of state-of-the-art biomarkers in PAIS, we identified alterations in amino acid, energy, and lipid metabolism as well as changes in the microbiome, mitochondrial stress, and the miRNA target network. All of these changes are directly and indirectly linked to the NF-κB pathway. The main altered molecules included IL-6, TNF, and IFN."

This summary was made using Gemini AI.

Study Overview

This study, published in BMC Immunology, investigates the cellular mechanisms behind Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Specifically, it looks at why the immune systems of ME/CFS patients often function poorly, focusing on a specific ion channel in Natural Killer (NK) cells and how its malfunction starves the cells' mitochondria of vital calcium (Ca2+).

The Biological Context

To understand the study, it helps to know how a healthy cell operates:

• Natural Killer (NK) Cells: These are frontline immune cells responsible for destroying infected or harmful cells. To kill a target, NK cells require a precisely timed flood of intracellular calcium (Ca2+).
• TRPM3 Ion Channels: Think of TRPM3 as a specific "gate" on the surface of the cell. When the cell needs to attack, this gate opens, allowing Ca2+ to rush into the cell body (the cytosol).
• The Mitochondria: Known as the powerhouse of the cell, mitochondria do more than just make energy (ATP); they act like sponges that buffer and absorb this rushing Ca2+. This Ca2+ absorption directly powers the cellular energy required for the NK cell to execute its immune functions.

The Problem: Previous research established that in ME/CFS patients, the TRPM3 gates are broken, leading to a weak influx of Ca2+ into the cell. This study takes it a step further to see how this broken gate impacts the downstream mitochondria.

How They Tested It

• Participants: The researchers took blood samples from 10 ME/CFS patients (diagnosed using strict clinical criteria) and 10 healthy controls (HC).
• Isolation: They isolated the NK cells from the blood samples to study them directly.
• Live Imaging: Using special fluorescent dyes that light up when they bind to Ca2+, the researchers were able to visually track Ca2+ moving into the main cell body (using a dye called Fluo-8 AM) and specifically into the mitochondria (using a dye called Rhod-2 AM).
• Chemical Stimulation: They used a chemical called Pregnenolone sulfate (PregS) to artificially force the TRPM3 gates open, allowing them to measure exactly how much Ca2+ made it through.

Key Findings

The researchers found distinct differences in how ME/CFS cells handle Ca2+ compared to healthy cells:

1. The Cell Body (Cytosol) is Starved of Calcium

• When the TRPM3 channels were stimulated to open, the NK cells of healthy patients showed a robust, healthy flood of Ca2+ into the cell.
• In ME/CFS patients, both the total amount of Ca2+ entering the cell and the speed at which it entered were significantly reduced.

2. The Mitochondria Are Compromised

• Because the main TRPM3 gate was failing to let enough Ca2+ into the cell, the downstream mitochondria in ME/CFS patients were consequently starved. The Ca2+ making it into the mitochondria via TRPM3 activation was significantly reduced compared to healthy controls.
• Interestingly, when the researchers bypassed the TRPM3 gate and simply flooded the environment with standard Ca2+, the ME/CFS mitochondria absorbed it much faster and in higher amounts than healthy cells. The researchers theorise this might be a compensatory mechanism; because the mitochondria are usually starved, they rapidly suck up any Ca2+ they can get, which can inadvertently lead to dangerous mitochondrial calcium overload.

The Big Takeaway

The results of this study heavily support the theory that ME/CFS is a "channelopathy", a disease fundamentally driven by malfunctioning cellular gates (ion channels).

Because the TRPM3 channels in ME/CFS patients are impaired, their NK cells cannot generate the massive Ca2+ signals required for normal function. Without this Ca2+, the mitochondria cannot produce the energy necessary for the NK cells to kill threats, explaining the immune system dysregulation commonly seen in the disease. Furthermore, because TRPM3 channels are found all over the body (including the brain and nervous system), this cellular dysfunction could help explain the wide array of sensory, cognitive, and fatigue symptoms that ME/CFS patients endure.

Link to 2026 study - https://link.springer.com/article/10.1186/s12865-026-00849-1

Major new ME/CFS research project launched in Europe: DISCOVER-ME, led by MedUni Vienna, has received over €7.5 million from the EU Horizon Europe program.

The project will run for four years and aims to improve ME/CFS diagnosis and treatment by identifying biomarkers, biological subtypes, and potential targeted therapies.

Researchers plan to analyze data from 2,000 patients, plus biological samples from more than 700 ME/CFS patients and nearly 200 controls, looking at immune, metabolic, hormonal, mitochondrial, proteomic, and epigenetic changes.

One especially interesting part: the project will use disease mapping, computer models, and “digital twins” to screen more than 9,000 existing drugs, narrowing them down to 20–50 promising candidates for future research.

This is exactly the kind of large-scale, biology-focused ME/CFS research we need: better diagnostics, patient stratification, and a path toward mechanism-based treatments.

Source: MedUni Vienna
https://www.meduniwien.ac.at/web/en/about-us/news/2026/news-in-june-2026/me/cfs-international-research-project-launched-under-the-leadership-of-meduni-vienna/

“A consortium led by the European ME Research Group (EMERG) has secured funding from the EU Horizon programme to support a major pan-European research project focused on myalgic encephalomyelitis (ME, sometimes referred to as ME/CFS). This award represents a significant advance in coordinated international biomedical research into ME following more than a decade of collaborative infrastructure development across Europe.”

Klimas gets 3 Million to investigate the connection between ME/CFs and mold exposure. Seems like we’re gonna get some decent data on the subject after all. Which personally I think is a good thing since there’s a lot of unscientific speculation about mold around. I hope he study is rigorous and uses reliable tests with rigid controls.

This summary was created using Gemini AI.

The study is a pivotal piece of research published in the International Journal of Molecular Sciences (IJMS, May 2026) by Dr. Alain Moreau and his team at the Université de Montréal / Open Medicine Foundation.

It offers an objective molecular explanation for Post-Exertional Malaise (PEM)—the severe symptom crash ME/CFS patients experience after minor exertion—proving it is rooted in biological "gridlock" rather than simple exhaustion.

1. Summary of the Paper's Analysis & Findings

The researchers wanted to track how ME/CFS patients adapt to physical stress at a cellular level. They evaluated 92 ME/CFS patients against 44 healthy controls, measuring blood markers before and after a specialized 90-minute mechanical stress test used to trigger a controlled, temporary PEM state.

The Two Core Competitors

• Irisin: An exercise-induced messenger (myokine) released by muscles during contraction. In healthy bodies, it protects mitochondria, boosts energy production, and suppresses inflammation by binding to α Vβ 5 integrin cell receptors.
• Thrombospondin-1 (TSP-1): A protein released during tissue stress and injury. In this pathway, it acts as a molecular "bully" that blocks irisin from doing its job.

Proposed model of impaired irisin responsiveness in ME involving TSP-1, αvβ5 integrin, and extracellular HSP90α-dependent mechanisms.

Key Discoveries

• Blunted Response at Baseline: ME/CFS patients started with significantly lower baseline irisin, and their bodies failed to produce the normal surge of irisin during stress (p < 0.05).
• The "Irisin Resistance" Paradox: Paradoxically, in moderate-to-severe patients, baseline levels of both irisin and TSP-1 were elevated, and high irisin was a direct predictor of fatigue severity (β = 0.728, p = 0.018). This means the body is desperately producing irisin to cope, but the signal is being ignored or blocked.
• TSP-1 is the Blocker: Using advanced cellular spectroscopy, the team proved that TSP-1 directly binds to and shuts down irisin signaling in a concentration-dependent manner.
• The Molecular Framework: Irisin requires the help of an intracellular chaperone, HSP90α, and the receptor α Vβ 5. When the researchers experimentally blocked α Vβ 5  or inhibited HSP90α, the cells completely lost their ability to counteract TSP-1, mimicking the exact cellular defects seen in severe ME/CFS patients.

The Takeaway: PEM isn't a psychological aversion to exercise; it is an "irisin resistance" state. When a person with ME/CFS exerts themselves, an abnormal spike in TSP-1 essentially locks the cellular doors, preventing exercise-induced irisin from delivering energy to the cells and clearing out inflammation.

Link to 2026 study - https://www.mdpi.com/1422-0067/27/11/4770

This summary was made using Gemini AI.

The Biological Premise: Autophagy and ATG13

To maintain cellular health, our bodies rely on autophagy—a highly regulated degradation pathway that clears out damaged organelles and misfolded proteins. A specific form of this, mitophagy, targets defective mitochondria (the cell's ATP/energy producers).

ATG13 (Autophagy-related protein 13) is a critical signaling protein. It acts as the ignition switch for the ULK1 kinase complex, which physically initiates the formation of the autophagosome (the cellular "garbage bag"). The researchers wanted to observe the systemic consequences when this initiation step is genetically impaired.

The Experiment

The researchers utilized a genetically modified mouse model where ATG13 was chronically depleted. By knocking down this single protein, they created an in vivo (living organism) model of stalled autophagy to observe the downstream metabolic, immunological, and neurological effects.

The Pathological Cascade

Depleting ATG13 triggered a massive, multi-system domino effect driven by metabolic failure:

1. Mitochondrial Dysfunction & ROS Accumulation

Because defective mitochondria were no longer being recycled via mitophagy, they began to accumulate in the cells. These damaged mitochondria were highly inefficient: their ATP (cellular energy) production plummeted, and they started leaking massive amounts of Reactive Oxygen Species (ROS)—unstable molecules that cause severe oxidative stress and damage surrounding cellular structures.

2. Immunometabolic Shifting (SIRT1 and NF-κB)

The spike in oxidative stress (ROS) acted as an alarm bell for the immune system, specifically targeting macrophages in the spleen. This triggered a profound shift in gene expression:

• SIRT1 Downregulation: SIRT1 is a crucial enzyme that promotes metabolic efficiency and healthy aging while keeping inflammation in check. In these mice, SIRT1 levels collapsed.
• NF-κB Activation: With SIRT1 out of the way, NF-κB (a primary transcription factor that drives inflammation) was activated. This caused the macrophages to shift into a chronic, highly aggressive pro-inflammatory state.

3. Peripheral Neuropathy (Nerve Demylination)

The combination of chronic systemic inflammation and rampant oxidative stress eventually breached the nervous system. The researchers observed demyelination—the degradation of the protective myelin sheath—specifically in the peripheral nerves that innervate skeletal muscles.

The Clinical Translation: ME/CFS and Long COVID

This paper is highly significant because it successfully models the underlying pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID.

The hallmark symptom of both diseases is Post-Exertional Malaise (PEM)—a severe, disproportionate exacerbation of fatigue, cognitive dysfunction, and muscle pain following minor physical or cognitive exertion.

The Takeaway: This study provides a concrete, molecular explanation for PEM. If a patient's autophagic machinery (like ATG13) is compromised, their cells cannot clear the metabolic waste (damaged mitochondria and ROS) generated by exertion. This local cellular failure triggers a systemic inflammatory loop and damages the nerves connecting to their muscles, literally stripping the body of its ability to produce sustainable energy.

Link to 2026 study - https://link.springer.com/article/10.1007/s00011-025-02158-6

Paper Analysis and Summary Made Using Gemini AI.

Title: Identification of Altered Potassium Channels for Drug Repurposing in Long COVID Patients Authors: John P. George, Kiran Bharat Gaikwad, Jyoti Sharma

Date: June 19, 2026 (bioRxiv)

1. Background and Objective

Long COVID (LC) is a complex, chronic condition characterized by persistent multisystem manifestations, with a notably high prevalence of neurological symptoms (e.g., brain fog, persistent fatigue). Human ion channels (HICs)—and potassium channels in particular—are abundantly expressed in the nervous system and are critical for cellular homeostasis and signal transduction.

The authors hypothesized that the dysregulation of these channels during and after SARS-CoV-2 infection plays a role in LC pathophysiology. The study aims to identify altered potassium channels in LC patients to serve as potential targets for drug repurposing.

2. Methodology

The researchers utilized a computational biology and transcriptomic approach:

• Data Collection: They performed a meta-analysis of bulk RNA-Seq datasets, specifically comparing gene expression profiles between patients who fully recovered from COVID-19 and patients experiencing Long COVID.
• Network Analysis: They constructed co-expression networks to group genes into functional modules and identify the relationship between altered HICs and broader biological pathways.

3. Key Findings

• Three Significant Gene Modules: The network analysis revealed three primary modules of dysregulated genes involving HICs, lipid metabolism, and immune signaling.
• Pathway Associations: These modules were strongly associated with immune-driven mechanisms, specifically:
  • Antigen processing and presentation
  • Complement and coagulation cascades
  • Cytokine-related signaling pathways
• Specific Drug Targets Identified: The analysis isolated four specific potassium channels that were significantly dysregulated and possess existing, approved pharmacological modulators:
  • KCNA6 (Voltage-gated potassium channel)
  • KCNJ10 (Inward-rectifier potassium channel)
  • KCNN3 (Small conductance calcium-activated potassium channel)
  • KCNH4 (Voltage-gated, delayed rectifier potassium channel)

4. Drug-Target interactions

From the total differentially expressed HICs identified, 10 were found to interact with approved drugs (Supplementary File 4). Of these 10 HICs, KCNN3, KCNA6, and KCNJ10 were from the blue module, and KCNH4 was from the brown module. KCNN3 was observed to interact with dequalinium. KCNJ10 interacted with mitiglinide, glipizide, tolazamide, and chlorpropamide. Additionally, both KCNA6 and KCNH4 were found to interact with amifampridine, guanidine hydrochloride, dalfampridine, and amifampridine phosphate.

https://preview.redd.it/l33qlzt3no9h1.jpg?width=858&format=pjpg&auto=webp&s=8bac7a1dc2071f6dc7dfda49e6f549388adbbf4b

5. Conclusion and Significance

The study concludes that persistent disruption of potassium homeostasis—driven by underlying immune dysregulation and chronic inflammation—is a likely contributor to Long COVID's neurological and systemic symptoms.

By identifying KCNA6, KCNJ10, KCNN3, and KCNH4 as key molecular targets, the authors provide a viable framework for drug repurposing. Using already-approved drugs that target these specific potassium channels could accelerate the development of new therapeutic interventions for Long COVID patients, pending further experimental validation.

List of drugs in the supplemental material here - https://www.biorxiv.org/content/biorxiv/early/2026/06/19/2026.06.18.733062/DC1/embed/media-1.zip?download=true

Link to 2026 study - https://www.biorxiv.org/content/10.64898/2026.06.18.733062v1.full

“This study demonstrated impaired glymphatic function in ME/CFS which may lead to symptoms such as cognitive dysfunction and sleep disturbance experienced by ME/CFS”

“We observed an association between the global DTI-ALPS index and severity of ‘sleep disturbance’ (p = 0.013, r = −0.47) and “impaired concentration” (p = 0.026, r = −0.43).”

That’s quite decent sized correlation for anything involving rating scales.

A brain scan study found higher AMPA receptor signals across much of the brain in people with Long COVID brain fog. AMPA receptors carry much of the brain's fast glutamate-based excitation, which makes nerve cells more likely to fire.

Also interesting is that they got 100% sensitivity and 91% selectivity. That’s much better than many purpose built attempts for biomarkers. This really looks like a solid finding.

“Therefore, the upregulated [¹¹C]K-2 SUVRWM in patients with Cog-LC may indicate increased surface-expressed AMPAR density. Therefore, non-competitive antagonists of AMPAR, such as perampanel, may be a therapeutic candidate for Cog-LC. This should be tested in future randomized controlled trials.”

And a potential treatment candidate lined up

Posted on X/Twitter here by user ME/CFS Science - https://x.com/mecfsskeptic/status/2063898792932347948

1. A research collaboration including Theoharis Theoharides and Nancy Klimas reports dramatically elevated levels of MMP-9, an enzyme that components of the extracellular matrix.

They previously reported similar results in Long Covid but I have doubts about their reliability.

2. MMP-9 was measured in serum (not in plasma) and there's a literature explaining why this isn't a reliable method. MMP-9 is released during the sampling and clotting process used to make serum.

3. One paper concluded for example "MMPs are released by platelets or leukocytes during platelet activation or sampling process, thus leading to artificially higher MMP-9 levels in serum..."

https://www.sciencedirect.com/science/article/abs/pii/S0009912006003237

4. The samples of ME/CFS patients and controls in this study were also handled and collected very differently. Patients were recruited at the University of Miami while the control samples were taken from an external biobank (bioBioIvt Elevating Science).

5. The authors note that "the samples had been stored for over ten years at -80 °C, which may have altered the fragmentation of certain biomarkers."

6. The 40 patients and 38 controls were all female but not properly matched (mean age was 51 in patients versus 43 in controls) and there's no info on other potential confounders such as BMI, medication use, etc.

7. So I have strong doubts about whether these results are reliable. The concentrations were 7 times higher in patients versus controls (126 versus 17 ng/ml), suggesting a technical artefact and differences in sample handling.

8 ) The authors also did a different experiment. They cultured mast cells and found that they release more MMP-9 when incubated with EBV-protein (representing viruses) or LPS (a component of the cell wand of bacteria).

9. In their Long Covid study they reported that MMP-9 was increased when cells from a microglia cell line where stimulated by Sars-Cov-2 spike protein.

Link here:

https://www.degruyterbrill.com/document/doi/10.1515/tnsci-2022-0352/html

10. Link to the paper:

Chinnapan et al. 2026. Elevated serum levels of interleukin-11 and matrix metalloproteinase-9 in myalgic encephalomyelitis/chronic fatigue syndrome.

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1827700/full

Clemson University studied 20 people and found Long COVID cells had a distinct metabolic signature, with weaker energy use and blunted responses to signals.

This points to bioenergetic dysfunction that may help explain fatigue. This lack of response to stimuli is also a repeating pattern from ME studies on exercise responses.

“The SARS-CoV-2 infection causes an over two-fold enhanced utilization of glycolytic and anaerobic substrates and a reduced response to growth factors and effectors. The increased energy source utilization assessed in PM-M1 is unsustainable, and the LC-19 groups demonstrate this with a clear correlation with the number of LC-19 symptoms, demonstrating a trend consistent with metabolic reprogramming.”

A Norwegian study replicated the finding that ME/CFS patients have more extracellular vesicles (EV) than healthy controls.

This may point to increased cellular communication and its contents might give us further clues

https://skywriter.blue/@mecfsscience.org/3mozf4iu7p52s

TLDR:

“Extracellular vesicles are tiny lipid particles that are released by cells and soft of act like mail carriers, transporting proteins, fats, and genetic material (RNA) from one cell to another.

Their contents might give a clue to what's happening inside the body.

Three 3 proteins that were increased (ITIH3, AMBP, and FGB) were liver-specific and expressed by hepatocytes. ITIH3 is involved in the stabilization of the extracellular matrix, while FGB is part of the
coagulation cascade

The EV proteins that were decreased in patients were mainly expressed by either red blood cells (specific to the bone marrow) or by plasma B cells (immune system-derived).”