Preprint Understanding Neuroinflammation in Post-COVID-19 Syndrome: Biological Mechanisms, Diagnostic Biomarkers, and Therapeutic..., 2025, Martins et al.

[rapidboson]

Abstract
Post-COVID-19 syndrome (PCS) is an escalating global health concern, marked by persistent cognitive, neurological, and psychiatric symptoms following acute SARS-CoV-2 infection. Although its underlying mechanisms remain incompletely understood, mounting evidence implicates chronic neuroinflammation as a key driver. Sustained microglial and astrocyte activation, blood-brain barrier disruption, and aberrant cytokine signaling contribute to prolonged immune dysregulation within the central nervous system, promoting long-term brain dysfunction.

In this expert review, we synthesize emerging insights into how neuroimmune processes impair brain function in PCS. We explore novel mechanistic pathways - including local sleep intrusions, impaired memory reconsolidation, and astrocyte-mediated destabilization of functional networks - that may underlie the syndrome's fluctuating and heterogeneous presentation.

We evaluate fluid biomarkers of neuroinflammation, including glial fibrillary acidic protein (GFAP), soluble TREM2, S100β, and pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-a. In parallel, we highlight converging neuroimaging biomarkers derived from PET and MRI studies. These include increased TSPO-PET binding in limbic and frontal regions, alterations in cerebral blood flow and oxygen metabolism, neurometabolic changes detected via MR spectroscopy (e.g., elevated myo-inositol and choline), and increased free water content on diffusion imaging - each suggestive of glial activation and network-level dysfunction.

We propose a multiscale, longitudinal framework that integrates molecular, neuroimaging, and behavioral data to link immune dysregulation with brain network instability and symptom emergence. Such integrative approaches are critical for advancing precision diagnostics and informing the development of targeted, mechanism-based treatments for individuals affected by PCS.

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[Creekside]

It's good to see some effort being made to better understand how glial cells cause symptoms, and how the vagus nerve also plays a part. Thsi sort of work also leads to improvements in brain imaging technology, leading to further discoveries of just what's going on in there.

Another benefit of this sort of research: it reduces the mystery that the BPS crowd depends on. If, for example, brainfog was clearly determined to be caused by a chemical ratio in astrocytes, any theories involving teddybear trauma can be discarded.

 

[SNT Gatchaman]

Personalized rehabilitation strategies tailored to the dynamic neurobiological state of each patient may also enhance recovery. Meeting this challenge will require sustained, cross-disciplinary collaboration among neurologists, psychiatrists, immunologists, sleep researchers, and rehabilitation specialists.

Table 1. Ten outstanding questions on neuroinflammation in PCS and suggested research approaches. […]

9. Which rehabilitation strategies most effectively support circuit reintegration, reconsolidation processes, and resilience to flare cycles?
Controlled trials of cognitive-behavioral and neuroplasticity based rehabilitation approaches

10. How can integrated multidisciplinary care models dynamically respond to fluctuating brain states and optimize long-term recovery in PCS?
Clinical pathway optimization involving neurology, psychiatry, immunology, and rehabilitation

Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Denmark Hill, SE5 8AF, London

[…]

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

 

[Sean]

Another benefit of this sort of research: it reduces the mystery that the BPS crowd depends on. If, for example, brainfog was clearly determined to be caused by a chemical ratio in astrocytes, any theories involving teddybear trauma can be discarded.

Nah. They will just twist the results to something like claiming that such findings are secondary consequences of avoiding activity, of the dysregulated psycho-neuro state, etc.

Whether they can continue being successful in doing so is another question.

 

[jnmaciuch]

Nah. They will just twist the results to something like claiming that such findings are secondary consequences of avoiding activity, of the dysregulated psycho-neuro state, etc.

Whether they can continue being successful in doing so is another question.

I have to agree even though it is depressing. If we find a definite biological cause, they will still say that their theories aren’t dualist so the biological state is maintained by dysfunctional thought patterns. They will continue to claim that spontaneous reversal of the biological disease state was induced by successful psychological intervention.

If we find a medication that works, they will say that plenty of mental health conditions respond to both pharmacological intervention and CBT. And then they will lobby insurance companies on the basis that 10 sessions of CBT is cheaper than whatever prescription treats ME/CFS.

I made my peace a while ago with the fact that we will probably never be able to fully discredit them and make them accountable for the wrongdoing. But the hope is that we can relegate them to a fully fringe position, like the people who claim that CBT cures fatigue in MS/lupus/what have you. And hopefully with adequate education and advocacy we can limit the vulnerable patients who are shuttled into CBT as part of a “cost-effective holistic management plan.”

 

[Utsikt]

I have to agree even though it is depressing. If we find a definite biological cause, they will still say that their theories aren’t dualist so the biological state is maintained by dysfunctional thought patterns. They will continue to claim that spontaneous reversal of the biological disease state was induced by successful psychological intervention.

If we find a medication that works, they will say that plenty of mental health conditions respond to both pharmacological intervention and CBT. And then they will lobby insurance companies on the basis that 10 sessions of CBT is cheaper than whatever prescription treats ME/CFS.

I think it will eventually die out through retirement, and/or they will move on to other «contested» diagnoses. And once people start getting cured, a substantial amount will have the energy to make their professional lives a living hell.

 

[jnmaciuch]

And once people start getting cured, a substantial amount will have the energy to make their professional lives a living hell.

That’s the goal

 

[Sean]

And once people start getting cured, a substantial amount will have the energy to make their professional lives a living hell.

Yep. The bill will come due.

 

[Yann04]

Thanks for digging into the tables @SNT Gatchaman .

A little surprised to see this. I thought Danielle Beckman [an author of this paper] was one of the “good ones”?

 

[SNT Gatchaman]

She very much is. But often paper sections are divided up and one person's section and thinking can end up being in contention with others. Sometimes paper writing groups form up with subsequent dropouts and later additions to the group, or the lead author wants a particular spin.

I was probably a bit unfair to this paper in this thread's initial comments, by highlighting those last table points 9 and 10, when points 1-8 are firmly biology focused. In fairness to myself though I did initially note the KCL affiliations and so started to make my post about being pleasantly surprised, perhaps a sea-change etc, but then: nope - not so fast.

---
Here are points 1-8 from table 1

1. What specific neuroimmune pathways are activated during persistent neuroinflammation in post-COVID-19 syndrome, and do they induce local sleep in cortical microcircuits?

Multi-omics analyses; animal models; EEG-fMRI studies of local sleep under inflammation

2. How do neuroinflammatory profiles differ based on initial COVID-19 severity?

Stratified longitudinal studies using biomarkers and neuroimaging

3. What is the progression and resolution timeline of neuroinflammatory markers post-infection, and how does this relate to symptom fluctuation and flare cycles?

Longitudinal observational cohorts with time-resolved biomarker sampling and digital phenotyping

4. Which neuroinflammatory biomarkers predict persistent neurological and cognitive symptoms, including those linked to reconsolidation failure or fatigue?

Prospective cohort studies and biomarker validation trials

5. Are genetic or epigenetic markers associated with susceptibility to neuroinflammation, local sleep phenomena, or reconsolidation impairments in PCS?

Genome-wide association studies (GWAS); epigenetic analyses linked to cognitive profiles

6. Can neuroimaging reliably differentiate neuroinflammatory patterns and local sleep signatures linked to specific symptom clusters?

Functional and structural neuroimaging studies (MRI, PET, mobile EEG)

7. Which immunomodulatory therapies most effectively reduce neuroinflammatory markers, support metabolic resilience, and stabilize network function?

Randomized controlled clinical trials; mechanistically informed pharmacological studies

8. Can targeting glial activation and adenosine signaling reduce sustained neuroinflammation and associated cognitive or emotional symptoms?

Preclinical experiments; clinical trials of astrocyte/microglia and purinergic-targeted therapies

 

[Jonathan Edwards]

I don't see anything insightful in the abstract. It sounds like the usual lumping together of popular memes to generate platitudes. I would bin the term neuroinflammation for starters.

 

[Trish]

Can someone expain to me what the paper's authors mean by neuroinflammation, and why the term is controversial?

 

[Jonathan Edwards]

I don't know if the authors say what they mean but they would probably include any evidence of microglial activation, T cell infiltration or local production of pro-inflammatory cytokines.

Neuroinflammation is controversial because it is too vague to be useful. The neurobiologists actually came to this conclusion themselves at a conference a while back - we discussed it here.

In simple terms true inflammation of brain tissue rapidly alters nerve cell function and that is immediately obvious as stroke or multiple sclerosis or coma or epilepsy. Acute brain inflammation in encephalitis usually leads to needing ICU and a ventilator. Chronic inflammation produces sever local disability like blindness or paralysis as in MS. In other diseases like Parkinson's and Alzheimer's microglia may be activated but that may simply be them clearing up the mess of the damage of the disease. I don't think we have much evidence for the microglia causing harm. Where we do have that evidence is in MS, where demyelination appears to be directly due to microglial activation.

T cells generally do not get into brains except as part of the white cell influx of inflammation for whatever reason. It seems that they may do intereting things near the hypothalamus but that would not be inflammation. When T cells traffic around their normal routes we do not call that inflammation.

There are certainly changes in brains in people who have had severe acute Covid but I have not yet heard of any evidence for inflammation contributing to the sort of post-Covid illness of interest here.

 

[rvallee]

I made my peace a while ago with the fact that we will probably never be able to fully discredit them and make them accountable for the wrongdoing.

I agree there will never be any accountability, but discrediting is inevitable. Beliefs about peptic ulcers being psychological were just as fanatical as they are with us, and they are simply never mentioned anymore, as if it never even happened. It takes no authority to enforce it, it happens organically.

Which is actually quite a drastic form of accountability: erasure, you never even existed, no one even acknowledges that you were around, they are too embarrassed to even say your name. It's like the famous Stalin picture with the dude who got erased from it. No one will remember any of the chucklefucks involved in this, or make any reference to their work. Notice how Wessely is both famous for his 'work' on ME/CFS, but also almost never mentions it, and it's literally never actually cited when he is awarded for it or in discussions about his long and 'influential' career.

Erasure is what they did, and continue to do, to millions of us, so it's no comfort, but the only reason there are few examples like this is because the profession is almost completely stagnant at trying to figure out what they don't already know about. But when it happens, it causes a complete break with the past, and it's something that doesn't regress, fortunately.