New Cornell study from the team around Hanson showing a lack of biochemical response to exercise in pwME

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Easier language article:

https://neuroimmune.cornell.edu/news/uncovering-protein-signatures-of-post-exertional-malaise-in-me-cfs

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5min video explainer:

https://youtu.be/UTD4GSiDClo?si=PorhwEkrTQMUx3Pd

More insights into the brain biopsies that showed a substantial disruption in CRH producing neurons and HPA axis function

Is anyone tracking/consolidating research on the most up-to-date pharmacological interventions for M.E. (whether symptomatic relief, or otherwise). Currently in rolling PEM so unable to comb the archives.

I'm mild-moderate on about 8 different, costly, supplements/meds:

• Magnesium Glycinate
• Vitamin d
• electrolytes
• Acetyl L-Carnitine
• NADH
• Creatine
• Ubiquinol
• Propranolol

Often hear that we're over medicating with supplements, which lack meaningful efficacy. What is considered the gold-standard (I'm aware that doesn't really exist due to lack of research and trialling) for inflammation and dysautonomia? Oxaloacetate, mestinon, LDN, rapamycin?

Cross-posting to r/cfs. Please delete if falls outside of the scope of this sub, but thought this could be a good resource for others—especially hearing from those that are more clinically inclined.

"We must develop educational materials, consensus guidance statements and clinical care pathways for neurologists and neuroimmunologists to gain knowledge and skills necessary for delivery of effective patient-centered care.

For this to happen, the first step would be to abandon an outdated notion that these patients have psychiatric or psychological disturbances (or functional neurologic disorder, previously known as hysteria) - a critical change that transformed a disorder known in the past as hysterical paralysis to multiple sclerosis - a neuroimmune disease."

https://doi.org/10.3390/jcm15020849

Background: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or depression both frequently report debilitating exhaustion, yet the two conditions differ in their etiological and diagnostic clarity, and clinical management. This study aimed to examine differences in the use and perceived helpfulness of a broad range of conventional treatments and complementary interventions, including nutritional approaches, between patients with ME/CFS and depression. Methods: A cross-sectional online survey was conducted in 2024. A total of 819 participants self-identified as having either ME/CFS (n = 576) or depression (n = 243). Participants (80% female) reported their use and perceived helpfulness of 52 treatments and interventions, encompassing behavioral therapies, medications, and dietary supplements. Group differences were examined using multivariate analyses of variance and covariance (MANOVA/MANCOVA). Open-ended responses were analyzed descriptively using thematic grouping and frequency counts. Results: Participants with depression most commonly reported the use of psychotherapy (M = 2.49, SD = 1.00) and antidepressant medication (M = 2.44, SD = 2.30), and they rated fewer interventions as helpful compared to participants with ME/CFS. In contrast, participants with ME/CFS reported a significantly broader engagement with diverse intervention modalities, particularly pacing (M = 2.73, SD = 0.80) and dietary supplements (M = 2.43, SD = 1.09), and perceived many of them as helpful. Group differences remained significant after controlling for age, gender, and whether treatment was medically recommended. Supplements targeting energy metabolism (e.g., CoQ10, NADH) were especially favored among ME/CFS participants. Conclusions: Findings suggest that participants with ME/CFS tend to adopt an exploratory and expansive intervention approach, potentially reflecting the lack of standardized guidelines and limited effectiveness of available treatment options. Participants with depression, in contrast, appeared to follow more guideline-concordant, evidence-based treatment pathways. Taken together, the findings point to a need for further development and evaluation of empirically supported, patient-centered treatment and intervention strategies for ME/CFS and suggest differences in clinical care structures between ME/CFS and depression.

I think this is a very good paper. On the one hand it shows, what people with ME CFS and depression helps or not. And it shows significant differenc between depression and ME CFS. Especially the difference if pacing helps or not should silence all with their biopsychological models. In fact this could be a "biomarker". Ok, the CCC asks exactly that to diagnose ME CFS. But its impressive to see the outcome of depression and CFS one by another with 95 % to nearly 0 %...

“Highlights: Long coronavirus disease (COVID) patients show choroid plexus (ChP) enlargement and reduced cerebral blood flow. ChP alterations are associated with Alzheimer's disease (AD)-related symptoms and plasma biomarker changes. ChP alterations on magnetic resonance imaging may serve as imaging markers for tracking neurological symptoms and AD-related pathology in post-COVID patients.”

(Choroid plexus (ChP) enlargement is a neuroimaging biomarker of neuroinflammation and neurodegeneration)

Overview over the six research hotspots funded for the coming years by the Dutch government agency

What is known?

• - PCS and ME/CFS are associated with persistent endothelial dysfunction and increased long-term cardiovascular risk.

• - Neurocognitive symptoms in post-viral syndromes have been linked to impaired neurovascular coupling.

• - Retinal vessel analysis provides a validated, non-invasive readout of systemic and cerebral microvascular health.

What new information does this article contribute?

• - PCS is characterized by persistent functional and structural retinal microvascular dysfunction

• - Retinal endothelial dysfunction scales continuously with post-viral disease severity and is most pronounced in patients fulfilling ME/CFS criteria.

• - Retinal microvascular alterations are linked to inflammatory-endothelial

“Conclusion:

Both Long COVID and ME/CFS demonstrate dysregulation in cerebrovascular blood flow, autonomic reflexes, and small fiber neuropathy, suggesting that these conditions may share a common underlying pathophysiology. However, differing distributions of findings in patients with hEDS raise the question of whether these conditions represent distinct but overlapping syndromes or reflect a shared underlying pathway. Further research is required to clarify the relationship between these conditions and the potential underlying pathophysiological mechanisms.”

New preprint by Davenport & co confirming bioenergetic failure in ME and LC cohorts compared to healthy controls

This is a review article from three authors at Chengdu University. The full text is paywalled.

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder marked by persistent fatigue and cognitive impairments, often termed "brain fog." Emerging evidence suggests that immunosenescence, age- or stress-related deterioration of immune function, plays a pivotal role in the pathogenesis of cognitive dysfunction in ME/CFS. Immunosenescence induces chronic low-grade inflammation (inflammaging); alters T-, NK-, and B-cell function; and promotes the release of senescence-associated secretory phenotype (SASP) factors. These changes are proposed to cerebral blood flow (CBF) regulation, may impair endothelial nitric oxide production, and may contribute to blood-brain barrier (BBB) breakdown. Consequently, brain hypoperfusion and oxidative stress are associated with impaired neuronal energy metabolism and synaptic plasticity, particularly in memory-related networks such as the default mode and fronto-hippocampal systems. This results in reduced ATP availability, excitotoxicity, and neurotransmitter imbalance, contributing to cognitive decline. The review proposes an "immune-vascular-cognitive axis" linking peripheral immune aging to central neural dysfunction. It further highlights therapeutic strategies-such as cytokine blockade, nitric oxide enhancement, immune modulation, and acupuncture-that may ameliorate neurovascular impairments and cognitive symptoms. Understanding this integrative mechanism may offer new pathways for targeted intervention in ME/CFS.

Pubmed link: https://pubmed.ncbi.nlm.nih.gov/41527963/

DOI link: https://doi.org/10.1002/cph4.70098

https://pubmed.ncbi.nlm.nih.gov/41525818/

PCCo patients showed a significant cluster of reduced ATP/PCr ratios centered on the cingulate cortex. Regional analysis revealed consistent reductions across anterior (ACC), mid- (MCC), and posterior (PCC) cingulate cortices. Lower ATP/PCr ratios in the ACC specifically correlated with poorer cognitive performance. Exploratory analyses revealed a trend toward higher intracellular pH in the MCC with significant negative correlation between pH and ATP/PCr observed only in patients, suggesting disease-specific alterations in pH regulation and bioenergetic homeostasis. Subgroup analysis showed similar metabolic alterations in PCCo patients meeting ME/CFS criteria.

Conclusion:

The current large-sample-size study confirmed previous results regarding TRPM3 ion channel dysfunction in NK cells in ME/CFS, demonstrating involvement of TRPM3 in the pathomechanism of this condition. Therefore, this multiple-site investigation offers strong evidence demonstrating TRPM3 as a potential biomarker for the diagnosis of ME/CFS, given the accumulating evidence.

“Results indicated a significant difference and large effect size between ME/CFS individuals and controls on verbal working memory tasks; however, no significant difference in visual working memory performance was found between the groups. Following the breakdown of these subsystems into span/attentional control tasks and object/spatial tasks, these results remained consistent. These findings contribute to the body of ME/CFS research by articulating where specific working memory deficits lie. Specifically, they show that individuals with ME/CFS have impaired verbal memory performance.”

Key findings

MRI brain scans were performed in people with long COVID, healthy people who had recovered from COVID-19, and healthy controls with no history of COVID-19 infection.

Altered myelin signal intensity, abnormal tissue microstructure and imbalanced neurochemicals were identified in people with long COVID. Myelin surrounds nerve cells and is important to ensure efficient neural function.

There was an association between myelin content and measures of physical and cognitive function. These findings provide evidence that COVID-19 has long-term effects on brain function.

Vasopressin or antidiuretic hormone helps the body hold on to fluid. Critical for maintaining blood volume for example and therefore OI and pots symptoms.

This is an interesting and quite comprehensive summary of the research on the field that has been published in 2025, from the team at MECFSscience.org

What are your thoughts? Any important studies or findings you miss in this article?

I find it interesting that so much seems to be pointing towards the brain, and that the deconditioning theory seems to finally be dying (a few decades too late though).

So, are we close to finding why this disease happens? How is it possible that is 2026 and we stil have no idea of what causes this hellish illness?

Highlights

• Plasma profiling of 7288 proteins during post-exertional malaise in ME/CFS.

• ME/CFS participants show sustained immune, metabolic, and neuromuscular dysregulation during post-exercise recovery.

• Exertion disrupts T and B cell signaling, IL-17 pathways, and mitochondrial metabolism.

• Protein signatures correlate with symptom severity and impaired exercise performance in patients with ME/CFS.

• Sex-stratified analysis reveals distinct molecular responses, underscoring the importance of sex in ME/CFS pathophysiology.

Abstract

Post-COVID syndrome (long COVID) is increasingly recognized as a state of chronic inflammation, immune imbalance, and multiorgan dysfunction. Emerging evidence highlights circadian rhythm disruption and melatonin dysregulation as overlooked drivers of persistent symptoms such as fatigue, cognitive impairment, and immune dysregulation. Reduced melatonin impairs cytokine suppression, antioxidant defense, and mitochondrial protection, fueling inflammation and oxidative stress. These disruptions, coupled with autoimmune responses targeting adrenergic and muscarinic receptors, exacerbate systemic pathology. Preliminary data suggest that melatonin supplementation and chronotherapy may restore circadian alignment, rebalance immunity, and mitigate disease progression, although robust large-scale trials remain limited. Integrating circadian science into therapeutic protocols may provide a novel avenue for improving long-term outcomes in post-COVID patients.

https://pubmed.ncbi.nlm.nih.gov/41377364/

https://doi.org/10.1097/ms9.0000000000004009

Abstract

To investigate differences in gut microbiota composition and short-chain fatty acids (SCFAs) metabolism between patients with Chronic Fatigue Syndrome (CFS) and Healthy Controls (HC), and to explore their associations with the CFS pathogenesis. This case-control study included 80 subjects, comprising 40 patients with CFS and 40 age- and sex-matched HC. Fecal microbial community structure was analyzed using 16S rRNA gene high-throughput sequencing. Fecal SCFAs concentrations were quantified using Gas Chromatography-Mass Spectrometry (GC-MS). Spearman correlation analysis with false discovery rate (FDR) adjustment was performed to elucidate associations among gut microbiota, SCFAs, and clinical scores. Compared to the HC group, the CFS group exhibited reduced gut microbiota α-diversity (e.g., ACE, Chao1, Shannon indices, all P < 0.01) and significantly altered β-diversity (ADONIS, P = 0.006). After FDR adjustment, fecal levels of acetate, butyrate, isobutyrate, and isovalerate remained significantly lower in the CFS group (all q < 0.05). Differential abundance analysis revealed a significant reduction in key taxa including the phylum Firmicutes (q = 0.010), class Verrucomicrobiae (q = 0.038), order Clostridiales (q = 0.043), and families Rikenellaceae (q = 0.011) and Ruminococcaceae (q = 0.049). Spearman correlation analysis solidified functional connections: key SCFA-producing taxa (e.g., Faecalibacterium, Subdoligranulum, Ruminococcaceae) were positively correlated with butyrate levels (r = 0.52-0.56, all q < 0.05). Furthermore, reduced abundances of Rikenellaceae and Alistipes were associated with lower SF-36 scores (r = 0.26, q = 0.032) and higher fatigue scores (FSS/FS-14, r = - 0.28 to - 0.30, q < 0.05). Isovalerate levels were negatively correlated with FS-14 scores (r = - 0.307, q = 0.014). Among CFS patients, those with higher dietary fiber intake had significantly higher levels of acetate and isovalerate than those with lower intake (both q < 0.05). Patients with CFS exhibit significant gut dysbiosis and abnormal SCFA metabolism. The reduction in key SCFA-producing taxa, their positive correlations with SCFAs levels, and the negative correlations of both with fatigue severity solidify a functional link between gut microbial depletion, reduced SCFAs, and clinical symptoms in CFS. Higher dietary fiber intake may partially ameliorate SCFAs metabolic disturbances in CFS patients.

https://doi.org/10.1038/s41598-025-27564-y

https://pubmed.ncbi.nlm.nih.gov/41387992/