Evidence of White Matter Neuroinflammation in [ME/CFS]: A Diffusion-Based Neuroinflammation Imaging Study 2026 Yu et al
jnmaciuch
Senior Member (Voting Rights)
I think its a reasonable assumption if you have reasonable likelihood of infiltration actually happening. What I'm puzzled by (and it seems I'm not alone in this) is how to interpret lower RF compared to controls when controls probably have no infiltration.
Yes that's my main thought--from the earlier glymphatics discussion, it seems like astrocytes serve as a buffer zone for water to help the parenchymal space maintain a fairly constant concentration. They do not change size fast enough to be particularly important to fluid flow but they have been observed to swell and contract dramatically. So my thought is that any restriction fraction seen in healthy brains is likely to represent what is stored in astrocytes.
I guess the question is what else? My instinct says it would have to be a small space enclosed in hydrophobic boundaries.
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ME/CFS Science Blog
Senior Member (Voting Rights)
There are two lines of dicussions.
One is about the statistics. We find it weird that there were more significant findings when confounders like age, sex, depression, anxiety were added to the model. It's possible that this happens but usually adding confounders like this will result in less significant results, not more. There were also some concerns that they excluded 9 ME/CFS patients that could not be matched to healthy controls and how these were selected.
The other discussion is about the interpretation of the data. The authors argue that their findings suggest neuro-inflammation but if we look those up they suggest the opposite.
- ME/CFS patients for example had relatively fewer water molecules that can move in any direction (isotropic) and are confined to tight spaces (restricted). Previous studies assumed that this might reflect water molecules trapped inside cells. So this measure could be seen as an indicator of immune cell infiltration, there being more cells. But in inflammation this measure is increased while in ME/CFS it was decreased.
- The same with water molecules that can move in any direction (isotropic) but aren't restricted. This has been used as an indicator of edema, water flowing into tissue. Some studies reported this to be increased in inflammation but in ME/CFS it was decreased.
- What was increased in ME/CFS was water molecules flowing in a particular direction (anisotropic). These are assumed to be water molecules in axons: they are trapped in a tube and can only go in one direction. In inflammation this is sometimes decreased but in ME/CFS it was increased.
Jonathan Edwards
Senior Member (Voting Rights)
That would fit with more extracellular water )assuming everything is proportions) but agree it doesn't fit with more cells.
Jonathan Edwards
Senior Member (Voting Rights)
There is lots of water in extracellular matrix that doesn't move much - bound to sulphate residues etc.. But if it exchanges with other compartments very quickly then the separate phase may not be apparent. I spent about ten years working on water compartments before MRI became available. The most important thing I learnt was how complicated and counterintuitive it all was, even if the biological solutions had a simple elegance. The next thing I learnt was that almost everyone working in the field of water phases in articular tissue had all their basic concepts wrong. But five years later they admitted their mistakes. My recent foray into brain water with various eminent Norwegian groups suggests that none of them understand diffusion!!
jnmaciuch
Senior Member (Voting Rights)
Ah okay I see the previous discussion about hindered fraction now. So the mystery is how you get a bigger proportion of extracellular water without an increased in hindered fraction
so it would have to be water in an extracellular matrix that doesn't exchange much with other compartments to end up in the restricted fraction
Jonathan Edwards
Senior Member (Voting Rights)
Yes. And if the recent literature on CSF flux that I have been reading is anything to go by it is quite plausible that the whole idea of these fractions and compartments is bad physical chemistry. The data will mean something but maybe not what these names imply. Mathematical modellers, in my experience, only too often fail to understand the dynamic geometry at fine grain.
jnmaciuch
Senior Member (Voting Rights)
And it seems like it would take a massive amount of ground work to be able to interpret correctly, if the findings aren't a proxy for neuroinflammation. Which seems more and more likely. If there is something here, my sense is that we'll make sense of it by working backwards once the mechanism of ME/CFS is already known, rather than being lead to the mechanism by these findings.
ScoutB
Senior Member (Voting Rights)
Technically I'm supposed to be good at math, they gave me a PhD. This is the first time in years I've been unfoggy enough to think about it though, so apologies for ramblingI'm not that good at math but I think the very free water (with diffusion > 2.5 μm2/ms) doesn't even enter their equation.
The second part represents the isotropic components, an integral from a to b where "a and b are the low and high diffusivity limits for the isotropic diffusion spectrum f(D)." Given the further explanation in the text, one is tempted to assume that a = 0.3 and b = 2.5 μm2/ms. That would explain why the free fraction is never mention in the paper.
Anyway, I think the bounds on this integral have to to be big enough to cover any water diffusion that could contribute to the signal the MRI machine sees for the math to work out**. So, I'd assume b at least goes up to 3 μm2/ms, unless they are confident a priori there's no free diffusion, I guess. But either way, something at least equivalent to what you're saying is true, because after they use this equation to figure out what the function f is, there is an additional step (which is kind of glossed over in the paper) where they use that function f to actually compute NII-RF (and the other values). And in that additional step they are ignoring the free fraction.
**Rough explanation of how I think the math works:
Suppose we knew there was no anisotropic diffusion, so the sum on the left is zero and we can ignore it. Then we can think of the integral on the right as (loosely speaking) adding up the amount of signal coming from each rate of diffusion D, and the sum of all that should equal the signal the MRI machine sees, S_k. For example, f(2.5) sort of represents how much water diffusing at D=2.5 μm2/ms is contributing to the signal. I'm also going to think of the integral as a sum so we can reason about it. Then that equation in the screenshot (really, the system of equations they are considering for k=1,...,K) becomes a system of equations of the form
MRI signal = sum of f(D) x exp(D), added up over all the possible diffusion rates D.
(where the MRI signal and exponential function differ for each k). Then they are doing some kind of fourier transform to figure out what f is from that system of equations. If the sum (really the integral) excluded some diffusion rate D that actually did contribute to the MRI signal, the f they get as a result would be artificially large in other places to compensate.