Evidence of White Matter Neuroinflammation in [ME/CFS]: A Diffusion-Based Neuroinflammation Imaging Study 2026 Yu et al

[DHagen]

Opposite. The dystrophic microglia found in that ME/CFS autopsy study are not ameboid (larger/much rounder). They are much closer to ramified than amoebic.

Are the images misleading in this regard or am I simply not understanding? I would have characterized the ME/CFS microglia in the image posted by @Casterofspells as "rounder" than the controls, though also smaller. Was this discussed in the presentation (I may simply need to revisit it) or is this your interpretation?

Edit: I see that the microglia were in fact described as "dystrophic" and "fragmented" - does "dystrophic" here carry a specific meaning that precludes also being "ameboid" or does it simply mean "misshapen" in a more generic sense?

 

[poetinsf]

Good to know we can get our microglia replaced! I can breathe a sigh of relief.

Sarcasm aside, it looked pretty gruesome the last time I looked, a sort of bone marrow replacement therapy in your brain. Even if possible, I'm sure it's a long, long way off.

If microglial cells are indeed the culprit, I think there are other possible therapies to tamper them down without resorting to extreme measures. Given some patients' experience with remission/relapse, there also could be a (yet to be found) switch to return diseased cells back to health. But we get getting way ahead of ourselves. We'll need to wait for the replication of this study as well as the publication of Younger's.

 

[jnmaciuch]

Are the images misleading in this regard or am I simply not understanding? I would have characterized the ME/CFS microglia in the image posted by @Casterofspells as "rounder" than the controls, though also smaller. Was this discussed in the presentation (I may simply need to revisit it) or is this your interpretation?

Sorry for the confusion—see post #152 for an example of ameboid. You’re right that the “dystrophic” microglia in ME/CFS are slightly rounder than the ramified if you only look at those two next to eachother, but it’s still a far cry from ameboid, which any researcher who knows microglial morphology would be easily able to distinguish. (Meaning that if the autopsy study showed ameboid microglia they would've just said that)

If a “heathy” ramified microglial cell is a spider with long spindly legs, a dystrophic cell is a slightly misshapen spider with weird stumpy or missing legs, and an ameboid cell is just a big fat coffee stain.

 

[DHagen]

Sorry for the confusion—see post #152 for an example of ameboid. You’re right that the “dystrophic” microglia in ME/CFS are slightly rounder than the ramified if you only look at those two next to eachother, but it’s still a far cry from ameboid, which any researcher who knows microglial morphology would be easily able to distinguish. (Meaning that if the autopsy study showed ameboid microglia they would've just said that)

If a “heathy” ramified microglial cell is a spider with long spindly legs, a dystrophic cell is a slightly misshapen spider with weird stumpy or missing legs, and an ameboid cell is just a big fat coffee stain.

Thank you - that's a big help!

 

[Jaybee00]

Sarcasm aside, it looked pretty gruesome the last time I looked, a sort of bone marrow replacement therapy in your brain.

Thanks for posting that paper.

 

[Hutan]

Are the images misleading in this regard or am I simply not understanding? I would have characterized the ME/CFS microglia in the image posted by @Casterofspells as "rounder" than the controls, though also smaller. Was this discussed in the presentation (I may simply need to revisit it) or is this your interpretation?

I shared DHagen's confusion at your posts @jnmaciuch. I think the autopsy results show a trend to less ramification of the microglia, which could conceivably explain the lower RF finding. I think when Qiang referred to amoeboid microglia he was just meaning 'round, without branching'. (I guess we need replication of everything before we can be sure of anything.)

Dystrophic microglia are specifically senescent, meaning not expressing any of the markers associated with the phenotypic state capable of pumping out cytokines.

Do you have a reference for that handy?

 

[jnmaciuch]

I shared DHagen's confusion at your posts @jnmaciuch. I think the autopsy results show a trend to less ramification of the microglia, which could conceivably explain the lower RF finding. I think when Qiang referred to amoeboid microglia he was just meaning 'round, without branching'. (I guess we need replication of everything before we can be sure of anything.)

I would be surprised if that’s what Qiang meant by ameboid if anyone on their team had experience with microglial morphology. The autopsy study suggests that there is a shape change, just not the one Qiang has in mind that would be more obviously consistent with a narrative of classic “neuroinflammation” pushed in the paper.

The diffusion coefficient change between a ramified and dystrophic cell would be much more minute than the change between a ramified and an ameboid. Given that we have no evidence of an increase in overall number of microglia, it would be profoundly surprising if that relatively small shape change is enough to produce a signal using an imprecise method where large interpersonal variability is expected. Impossible? No. But also not much in support of it over other possible explanations

Do you have a reference for that handy?

it was described as senescent by a colleague who studies microglia, and that’s what senescent means in an immune context. That would’ve been based on cell surface markers. As in any field of science it’s possible new information could come to light and challenge some assumptions about the classification. Still, no matter how you slice it, it is quite hard to fit these findings with a narrative of classic neuroinflammation

 

[butter.]

I would be surprised if that’s what Qiang meant by ameboid if anyone on their team had experience with microglial morphology. The autopsy study suggests that there is a shape change, just not the one Qiang has in mind that would be more obviously consistent with a narrative of classic “neuroinflammation” pushed in the paper.

The diffusion coefficient change between a ramified and dystrophic cell would be much more minute than the change between a ramified and an ameboid. Given that we have no evidence of an increase in overall number of microglia, it would be profoundly surprising if that relatively small shape change is enough to produce a signal using an imprecise method where large interpersonal variability is expected. Impossible? No. But also not much in support of it over other possible explanations


it was described as senescent by a colleague who studies microglia, and that’s what senescent means in an immune context. That would’ve been based on cell surface markers. As in any field of science it’s possible new information could come to light and challenge some assumptions about the classification. Still, no matter how you slice it, it is quite hard to fit these findings with a narrative of classic neuroinflammation

In regards to dystrophic microglia in isolation, the absence of a classical cytokine signal in chronic ME/CFS does not mean there was no inflammation. It may simply mean we are looking too late, after an earlier inflammatory phase has already faded. Personally, I find this extremely likely. In that sense, what we are doing in ME/CFS is a bit like studying and treating (that's actually the really insane part) stroke patients six months after the event and trying to infer the acute biology from that.

The little temporally stratified data we do have in ME/CFS suggests, at least in part, that inflammatory signals are more present early and less obvious (or seemingly 'depleted') later. At the same time, there are interesting SARS-CoV-2 models in mouse and golden hamster showing how peripheral inflammation can drive central neuroimmune changes, even without direct invasion. We tend to leave that kind of biology aside for some reason. Maybe there are good reasons?

'We' (definitely not my idea! ) have effectively decided to anchor diagnosis at six months, mostly for practical reasons around reducing misdiagnosis (in part sensible), not because it reflects a clear biological boundary. If anything, if you really wanted stability, you might argue for one or even two years for diagnosis if you really want to differentiate PVFS and ME/CFS. But as a result, we systematically miss the early phase where these inflammatory dynamics are most likely to be visible. At least for research purposes, we have to start looking at the acute phase.

 

[Violeta]

Dystrophic microglia are specifically senescent, meaning not expressing any of the markers associated with the phenotypic state capable of pumping out cytokines.

Thank you for clarifying that the cells are probably senescent.

"Senescent cells are known to secrete a variety of bioactive molecules, collectively termed the senescence-associated secretory phenotype (SASP). These molecules include pro-inflammatory cytokines, growth factors, and proteases, which can contribute to chronic inflammation and tissue degradation, ultimately leading to the development of conditions such as cardiovascular disease, arthritis, and neurodegenerative disorders. Additionally, SASP molecules reduce nicotinamide adenine dinucleotide (NAD+), an important coenzyme involved in redox reactions, DNA repair, and energy metabolism."

The Role of Senescent Cells in Longevity and How to Reduce Their Impact

www.vailhealth.org

Do you think that there is a lack of adequate efferocytosis causing the senescent cells to be hanging around?

Senescent immune cells spread damage throughout the aging body​

https://www.nia.nih.gov/news/senescent-immune-cells-spread-damage-throughout-aging-body

 

[Violeta]

I realize that senescense is not unusual, but besides ineffecient efferocytosis, should we look for a possible reason for the microglial senescense.

Are there any signs of or reasons for oxidative stress in the brains of those with ME/CFS?

Does anyone know other possible reasons?

Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons​

https://pmc.ncbi.nlm.nih.gov/articles/PMC12383077/

"Cellular senescence, a state of permanent cell cycle arrest, represents a double-edged sword in biology—providing tumor-suppressive functions while contributing to tissue degeneration, chronic inflammation, and age-related diseases when senescent cells persist. A key driver of senescence is oxidative stress, primarily mediated by excessive reactive oxygen species that damage mitochondrial DNA, modulate redox-sensitive signaling pathways, and trigger the senescence-associated secretory phenotype."

"Emerging evidence highlights the pathogenic role of SASP in promoting local inflammation, immune evasion, and senescence propagation."

 

[Jonathan Edwards]

Are there any signs of or reasons for oxidative stress in the brains of those with ME/CFS?

I think there is a danger of going off on a wild goose chase in response to papers about things like oxidative stress and cell senescence. There are always a bunch of papers to support any speculation in this sort of area.

On a broad front I don't think we have much reason to think there is much wrong with microglia in ME/CFS brains. Certainly I don't think this study is likely to be telling us much about microglia.

 

[jnmaciuch]

Thank you for clarifying that the cells are probably senescent.

I should clarify that senescent is a context-specific term, especially when relating to immune cell types. My main point is just that it’s considered distinct from the typical “activated” state that most immune cell types have, which is the one associated with the greatest cytokine production and sometimes an identifiable morphological state.

It’s theoretically possible that these dystrophic microglia release some cytokines. If this was a driving feature of all ME/CFS, however, the question is why we don’t see strong differences in cytokines in cerebrospinal fluid. It’s really hard to argue that there’s temporal fluctuation and we’re just not measuring at the right time when you’re claiming the cytokines come from a global shift in microglial state.

Do you think that there is a lack of adequate efferocytosis causing the senescent cells to be hanging around?

I agree with Jonathan, if there are senescent microglia it seems more likely that they are downstream of another problem rather than causing ME/CFS. I think the same goes for any potential differences someone could tie to efferocytosis—maybe some parts of it are slightly impaired by the actual disease process (potentially explaining, for example, higher concentration of lingering SARS-CoV-2 fragments inside phagocytotic cells), but it’s quite difficult to see how it would be driving this illness.

 

[Violeta]

if there are senescent microglia it seems more likely that they are downstream of another problem rather than causing ME/CFS

I agree. That's what I'm looking for. Do you have any ideas where to look?

 

[jnmaciuch]

In regards to dystrophic microglia in isolation, the absence of a classical cytokine signal in chronic ME/CFS does not mean there was no inflammation.

You may be right, it might be something that only occurs during the acute infection in infection-onset ME/CFS. But unless there was permanent irreversible damage (which I think we’ve already discussed ad nauseum across the forum and it seems unlikely), that’s not the state that drives decades worth of symptoms in ME/CFS. You could theoretically argue that understanding the initial “inflammatory” state, if it exists, maybe could be useful for understanding what comes after. My perspective is that it wouldnt be any more helpful than just focusing on the “what comes after”

 

[jnmaciuch]

I agree. That's what I'm looking for. Do you have any ideas where to look?

From what I understand the idea of “dystrophic” microglia is pretty new, compared to ameboid and ramified which are the two classic states we’ve known about for years. So unfortunately we don’t have much information about what causes a dystrophic state yet.

 

[Violeta]

You may be right, it might be something that only occurs during the acute infection in infection-onset ME/CFS. But unless there was permanent irreversible damage (which I think we’ve already discussed ad nauseum across the forum and it seems unlikely), that’s not the state that drives decades worth of symptoms in ME/CFS. You could theoretically argue that understanding the initial “inflammatory” state, if it exists, maybe could be useful for understanding what comes after. My perspective is that it wouldnt be any more helpful than just focusing on the “what comes after”

I'm thinking about oxidative stress.

 

[jnmaciuch]

I'm thinking about oxidative stress.

In what context? I think oxidative stress gets tossed around often as a bit of a bogeyman. If it’s at all relevant here, you’d need to explain what cell types it occurs in, what maintains it for years, and how it actually explains the symptoms of ME/CFS.

 

[Violeta]

In what context? I think oxidative stress gets tossed around often as a bit of a bogeyman. If it’s at all relevant here, you’d need to explain what cell types it occurs in, what maintains it for years, and how it actually explains the symptoms of ME/CFS.

Do you know of any studies about oxidative stress with respect to ME/CFS?

First time I've heard oxidative stress with respect to ME/CFS called a bogeyman.

 

[jnmaciuch]

Do you know of any studies about oxidative stress with respect to ME/CFS?

The most recent one off the top of my head is in this thread:

Thread 'Oxidative Stress is a shared characteristic of ME/CFS and Long COVID, 2025, Shankar, Bonilla, Davis et al.'

May 6, 2024

Preprint, see post #39 for peer-reviewed version
-------------------------------------------------------------

Oxidative Stress is a shared characteristic of ME/CFS and Long COVID
Vishnu Shankar; Julie Wilhelmy; Basil Michael; Layla Cervantes; Vamsee Mallajosyula; Ronald Davis; Michael Snyder; Shady Younis; William H Robinson; Sadasivan Shankar; Paul Mischel; Hector Bonilla; Mark Davis

More than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional...

• SNT Gatchaman
• calcium glutathione gpx4 lipid droplets lipids mark davis metformin mitochondria oxidative stress reactive oxygen species ron davis sex differences t cells
• Replies: 46
• Forum: ME/CFS research

• 

I would take the author's interpretation of their data with a hefty grain of salt. And also note that "oxidative stress" in circulating immune cells doesn't tell us much about oxidative stress anywhere else.

First time I've heard oxidative stress with respect to ME/CFS called a bogeyman.

Yeah unfortunately it took me becoming a trainee scientist myself to fully realize I can't inherently trust the majority of the science I read (let alone what MDs, patient advocacy orgs, or other people on the internet have to say about it). Oxidative stress has become something that a lot of people will cling to as inherently bad and disease-causing, without much understanding at all of how it functions biologically. It's real, you can assess it in multiple ways, and also 90% of the time it doesn't mean what people claim it means. I've had the benefit of having my own assumptions challenged by Navdeep Chandel's work, a scientist at my university who's done more foundational work on oxidative stress than arguably anyone else alive.

 

[Jonathan Edwards]

Do you know of any studies about oxidative stress with respect to ME/CFS?

First time I've heard oxidative stress with respect to ME/CFS called a bogeyman.

Michael Maes has been going on about oxidative stress in ME/CFS for years. Others have invoked it. I remember it being all the rage 50 years ago. And never discovered why anybody was interested in it.