Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans. Thapaliya et al. 2020

https://www.sciencedirect.com/science/article/pii/S2213158220302035

 

This is from the Griffith University group, and particularly L Barnden who is probably the most prolific brain imager in me/cfs.

They pre-identified 46 areas of interest and the most interesting finding looks to be

However, the mean differences are not big (one big numbers corresponding to brain region CST-L looks like a typo that should be .[0]9. But it may be that t1w/tw2 numbers are quite constant and low so that small changes are a bigger deal. For example, I'm trying to find what lower numbers would look like in MS, for comparison.

The authors aren't sure if it's due to iron increases or myelin increases.

 

This study is novel in that the active MRI tasks was the stroop test. The magnitude of the observed effect may suggest that this is a consequence, rather than a cause of the dysfunction in ME.

Notably the T1w/T2w artifacts were noted to be in the opposite direction as observed in multiple sclerosis.

I'm not sure what to make of this. I don't much care about the regressions with HRV (especially scince there was no difference in HRV between patients and controls), or respiration rates.

The regressions for the stroop test were the Postcentral gyrus and the Middle temporal gyrus, both areas involved in visual image processing (eg lesions associated with dyslexia, inability to recognise Chinese logograms.)

So nothing much unexpected there.

Discussion of the artifacts due to increased myelin or iron, is uncertain, though I lean towards the latter since I believe the abnormalities arise from disturbed endothelial function or dysregulation of extracellular matrix factors (I wish I could be more specific on this). Increased iron is associated with increased oxidative stress and endothelial dysfunction in general.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327076/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496698/

Most cellular iron is absorbed via https://en.wikipedia.org/wiki/Transferrin_receptor
Iron-sulfur proteins are quite important for cellular functions: https://en.wikipedia.org/wiki/Iron–sulfur_protein

"Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1963417/

https://en.wikipedia.org/wiki/Neuroferritinopathy

"Deep Gray Matter Iron Deposition and Its Relationship to Clinical Features in Cerebral Autosomal Dominant Arteriopathy"
https://pubmed.ncbi.nlm.nih.gov/32397933/ (https://en.wikipedia.org/wiki/CADASIL)

 

Does this mean we need a med that crosses the blood brain barrier to treat our pathological brains? Or will fixing the non-brain issues subsequently fix the brain?

Nimodipine (calcium channel blocker) crosses BBB
Cyclophosphamide crosses BBB

 

What could it mean for symptoms to the casual reader? this is a complex article.

 

Doesn't the increased myelin finding speak to that other study that showed increased myelin in and around the brainstem?

And wasn't the theory in that paper that this might be a compensatory mechanism caused by reduced signal between brain areas?

Mainly thinking aloud, but the studies might be connected?

 

I'm not sure if this has any relevance to these findings but didn't Ian Lipkin mention about a problem with iron metabolism/uptake during his CDC presentation:

https://cfsformecfs.org/2020/03/25/a-microbe-hunter-turns-to-me-cfs/amp/?_twitter_impression=true

He mentioned in his presentation (copied directly from the transcript):

35:54 (For animations, please refer to youtube presentation)

So I’m just going to demonstrate for you the ways in which we’re beginning to tease this apart. When we began looking at the most remarkable findings, at least to our mind, we found that they were related to iron metabolism. Now if you look at the methylation differences, you know, they’re modest, 12%, 11%, I don’t know how important that is. You then, we actually then measured RNA abundance so we created real-time PCRS so that we could actually look at the products of those methylated genes, and although no one gene is affected in a great fashion, if you sum them all, they could have a profound effect. So this is where we slip into fantasy, and I’ll show you what we think is going on.

36:42

So and this is moving into the cell, in this case we’re talking about monocytes and macrophages and somatic tissues, rather than red blood cells.

36:55

So we have our first lesion here, right? We have a lesion at the level of the clathrin coded pits. We have another lesion as these iron molecules are exiting the endosome–

37:09

You can see here now on the mitochondria, there’s an effect as it moves into mitochondria.

37:29

So in essence, what happens is you have an impact on multiple levels which should have an impact on your ability to metabolize oxygen and this could result in weakness and fatigue.

37:43

And we have to do the same thing with all of these circuits we’ve identified using all of these different methods and as we’re putting this thing together, it begins to look sort of like an anemia of chronic disease, with red blood cell damage and so forth, oxidated, stress. And this is a model that’s still in the process of being worked out.


I can't work out if this fits or not or is contradictory...

 

I'm still trying to work it out. The diagram is suggesting lower ferric->ferrous conversion (STEAP3), it is implying lower uptake by TfR1 & DMT1, but no data for DMT1 or TfR1 was provided, so this lowered uptake is assumed to be due to imparied vesicle endocytosis. The last diagram implies lower uptake into the mitochondria due to lower MTFN1.

(also keep in mind that this is the epigenetics of PBMCs and shouldn't necessarily be generalised to other cell types - when the actual gene expression was measured for specific genes, the increase in methylation led to lower expression)

From Table:

ALAS2 = Delta-aminolevulinate synthase 2 (catalyzes the first step in the heme biosynthetic pathway in mitochondria) "potential upstream target"

AP2A2 = AP-2 complex subunit alpha-2 (involved in clathrin-dependent endocytosis)

APOA1 = From Wikipedia: "The protein, as a component of HDL particles, enables efflux of fat molecules by accepting fats from within cells (including macrophages within the walls of arteries which have become overloaded with ingested fats from oxidized LDL particles) for transport (in the water outside cells) elsewhere, including back to LDL particles or to the liver for excretion."

AHSP = ERAF = alpha hemoglobin stabilizing protein

ARRB2 = Beta-arrestin-2 (agonist-mediated desensitization of G protein-coupled receptors)

HBA = Hemoglobin A "potential upstream target"

HBB = Hemoglobin B "potential upstream target"

HMOX1 = heme oxygenase (decycling) 1 "potential upstream target"

HTT = huntingtin protein (Wikipedia claims functions including vesicle trafficking and inhibition of mitochondrial electron transport)

STEAP3 = From Wikipedia: "metalloreductase, capable of converting iron from an insoluble ferric (Fe3+) to a soluble ferrous (Fe2+) form"

MTFN1 = mitoferrin-1 (references as MTFN1 are rare), transports ferrous iron into intermembrane space of the mitochondria



From diagrams:

DMT1 = divalent metal transporter 1 (Transports ions in 2+ oxidative state, according to Wikipedia, expression is regulated by body iron stores to maintain iron homeostasis.)

TfR1 = Transferrin receptor 1

 

CAI Seminar Series: Detection of brain dysfunction in CFS using multimodal brain MRI
Detection of brain dysfunction in Chronic Fatigue Syndrome using multimodal brain MRI: Presented by Dr Leighton Barnden, Imaging Consultant, National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University. Presented 20 October 2020.

Code:

https://www.youtube.com/watch?v=0H5UJQSa0l0&feature=youtu.be

 

CADASIL is extremely rare
My gene PITX2 targets NOTCH3 so maybe I have a partial deficiency and an effect on blood vessels
Mutation of FOXC1 and PITX2induces cerebral small-vessel disease
https://www.ncbi.nlm.nih.gov/sites/...QZEnLJ37FxFidR2JQ5LAxxMBntAe325Pqbo9exAbusHl4

https://www.frontiersin.org/articles/10.3389/fcvm.2021.681948/full
The Notch Pathway: A Link Between COVID-19 Pathophysiology and Its Cardiovascular Complications