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

Discussion in 'BioMedical ME/CFS Research' started by John Mac, Aug 3, 2020.

  1. John Mac

    John Mac Senior Member (Voting Rights)

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

    dreampop Senior Member (Voting Rights)

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    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.
     
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  3. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    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)
     
    Last edited: Aug 4, 2020
  4. Jaybee00

    Jaybee00 Senior Member (Voting Rights)

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    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
     
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  5. Hutan

    Hutan Moderator Staff Member

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    For those of us tripping over the terminology in the very first sentence:
    https://www.radiologymasterclass.co.uk/tutorials/mri/t1_and_t2_images

    MRI interpretation
    T1 v T2 images

    Key points
    • On T1 images FAT is white
    • On T2 images both FAT and WATER are white
    It’s all about FAT and WATER
    The two basic types of MRI images are T1-weighted and T2-weighted images, often referred to as T1 and T2 images.
    The timing of radiofrequency pulse sequences used to make T1 images results in images which highlight fat tissue within the body.
    The timing of radiofrequency pulse sequences used to make T2 images results in images which highlight fat AND water within the body.

    So, this makes things easy to remember.

    T1 images – 1 tissue type is bright – FAT
    T2 images
    – 2 tissue types are bright – FAT and WATER
    So iron also contributes to the brightness in both types of image?

     
    Last edited: Aug 4, 2020
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  6. garden

    garden Established Member

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

    Hutan Moderator Staff Member

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    Apologies for thinking aloud and before I actually read the posted paper...
    Myelin is fatty, so a high T1/T2 ratio could suggest lots of myelin.

    Re iron:

    From this 2020 paper:
    Ratio of T1-Weighted to T2-Weighted Signal Intensity as a Measure of Tissue Integrity: Comparison with Magnetization Transfer Ratio in Patients with Multiple Sclerosis
    Given the 2020 date, it sounds as though the T1/T2 ratio is a relatively new thing, with the significance of the ratio still being worked out.
     
  8. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    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?
     
  9. jaded

    jaded Established Member (Voting Rights)

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    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...
     
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  10. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    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
     
  11. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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    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
     
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