50+ shades of grey matter

5

One of the commonest myths about the brain is that we use only 10% of it. The origin of this probably goes back to the unsung hero of neuroscience, William James, when he was jokingly commenting on the fact that the functioning neurons sum up to only 10% of the brain cells and the 90% are supportive cells.

Grey matter looks darker because it contains more dense aggregation of cells

The grey matter carries most of cells in the nervous system (the 10%+90% cells) as well as the extensive connections between these cells. Loss of these cells and their connections has been associated with disability of MS more than to white matter broadly speakig.

Grey matter is vulnerable to damage

Sometimes (personal opinion) I like to imagine grey matter as a busy odd looking scientist who needs silence and quite environment to do his work, but the immune reactions taking place around him keeps him distracted. Presence of a continous ongoing immune reaction within the nervous system is toxic to the grey matter, and the orchestrating complex function of the grey matter gradually collapse.

Grey matter is vulnerable once immune activation takes place within the nervous system

Grey matter pathology is well evident in MS, as well as other disease conditions that result in continous immune activation within the nervous system compartment, such as infections, and systemic autoimmune conditos,

Grey matter damage in MS

Grey matter structures such as the “thalamus” loses an observable amount of its volume in the early phase of the disease. Focal damage at that time is not stong enough to interpret such atrophic changes.

Grey matter loss in MS (deep grey matter in particular) has been recently linked to higher unemployment, even after adjustment for age, education and disease duration.

There cerebral cortex also suffer various form of damage. Brain coverings in MS host special collections of immune cells termed “lymphoid follicles” which maintains a level of continous damage and support to other immune cells. It is belived the chemicals secreted at these follicles, antibodies and cytotoxic cells all exert a direct damage to their nearest neighbour “the cerebral cortes. Subpial demyelination, cortical thinning and regional atrophy among many other forms of damage is observed frequently in progressive phase of the disease.

Spinal cord matters too

Recently, these very “lymphoid follicles” has been well observed in the coverings of the spinal cord in secondary progressive MS (SPMS). Comparing SPMS patients who showed lymphoid follicles to those who did not, CD20 B lymphocytes were 3 times more abundant within the meningies, perivascular spaces as well as grey and white mater. Other immune cells such as the antibody producing cells, T cells, and macrophages were present in abundance as well. Grey matter demyelination in the spinal cord was more pronounced than white matter, a number of studies show that grey matter demyelination causes significant neuronal and synaptic loss.

This is particularly interesting observation in MS because progressive loss of walking ability is one hallmark of the disease. The continous damage to grey matter of the spinal cord is different from that of the brain in one particular fact, the spinal cord has much less tissue and cells to withistand continous inflammation for long time. The whole spinal cord thickness is slightly larger than your little finger.

Spinal cord atrophy measued by MRI is strongly associated with disability progression independently from what is taking place upstairs in the brain. Grey matter atrophy of the spinal cord has been the most to correlate with disability using MRI in a number of other studies.

It is difficult to translate what we see in pathology studies directly to in-vivo MRI findings, as loss of cord volume does not necessarily reflect cell loss but both are linked and point towards the fact the spinal cord pathology is a main determinant to disease outcome and needs to be put as a priority in assessing disease trajectory on individual patient level.

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Dr Wafa

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  • Interesting stuff, thanks for posting! I have been diagnosed with PPMS in 2019. 3 lesions in the spinalcord and nothing in the brain. Are lesions in the spinalcord always associated with significant volume loss or can you 3 medium lesions with little loss of volume. Next appointment with my neurologist I hope to get some answers regarding BVL and SCVL.

    • Hello Paul

      Cord atrophy relation to visible MRI lesion is weak indeed.

      Only with extensive lesions you may find a correlated significant atrophic changes.

      Best of Luck with your fight with MS 🙂

    • That’s what I’d like to know about lipoic acid.

      It’s an anti oxidant yes, however there are lots of anti oxidants.

      Is it that it’s slowing down T cells getting into the CNS to cause damage. It may have a dual action.

      With a lot of talk about smouldering MS, we have a natural molecule that is showing in phase 2 to reduce brain atrophy in MS by 68% !!!!! which is massive. And there seams no urgency to get it out there to further larger trails. Maybe because it’s a natural molecule and not man made and billions cannot be made form it.

      • BTW I’m not really sure it’s fair to blame pharma for not funding alpha-lipoic acid trials. How can they stay in business if they spend hundreds of millions of dollars on treatments which will earn them nothing? It’s not as though they have charters granting them a monopoly on pharmaceutical research, if anything we should be blaming governments and the MS societies for not funding these trials and instead wasting money on useless EAE studies and snake oil like CCSVI.

        • Agreed, however if the ultimate goal is to stop smouldering MS and further disability, it just seams like plenty of small trails and nothing definitive.

          Natural molecules will never be considered a treatment.

          I mean how many phase 2 trials can you do for it to be considered effective and clinicians recommend taking it.

          vitamin d is the same. Is it beneficial or not. Most likely but there will never be a trial big enough to confirm.

    • I think there is some evidence that it has a direct impact on the inflammatory milieu via action on T cells, however presumably most of the neuroprotective effects are indirect if it is indeed effective at slowing BVL in advanced MS. In other words, I don’t think it is directly targeting B cells or lymphoid follices but rather supporting brain tissue and helping more of it survive the ongoing damage.

  • A scary post if you have MS!

    “Comparing SPMS patients who showed lymphoid follicles to those who did not, CD20 B lymphocytes were 3 times more abundant within the meningies, perivascular spaces as well as grey and white mater. Other immune cells such as the antibody producing cells, T cells, and macrophages were present in abundance as well.”

    Are the lymphoid follicles within the CNS?

    How does this fit with the Sizomus study which is looking at killing off plasma cells in the CNS? Will the drug being tested have any impact on these other immune cells and macrophages?

    • Hello SID

      Lymphoid follicles have been observed within the coverings “meninges” of the brain and spinal cord. It provides a strong evidence that immune cells reside within the CNS.

      I can imagine that this is highly relevant to SIZOMUS and antiplasma cell therapy, as the drug is a small molecule and is expected to attack plasma cells living within the nervous system.

      Ixazomib “SIZOMUS drug” target primarily plasma cells, but no well known effect to other immune cells. the proteosome system is important for maintainance of the massive antibody production line within plasma cells, and once interrupted cells undergo apoptosis (programmed cell death).

  • Thanks for posting!

    Hopefully long, quality sleeps will help CSF to flush out the inflammating chemicals every night!..

  • Dr Wafa,

    Thanks for the post.

    “I like to imagine grey matter as a busy odd looking scientist”. Do you mean like MD1?

    You refer to “continous immune activation within the nervous system compartment, such as infections, and systemic autoimmune conditions”. So, if there is an infection in the CNS eg EBV, isn’t the immune system just doing what it should be doing ie trying to get rid of the infection? If drugs eg ixazomib, BTK inhibitors, are used to get rid of the immune cells responsible for the continuous immune activation, they will not be addressing the root cause of the problem ie the infection, so won’t the problem just come back ie the immune response will come back as the infection is still there.

    • MD1 is one of my best good looking scientist I have ever seen 🙂 I am one of his fans personally.

      EBV is obviously linked but we can not confirm exactly how it exerts its bad effect.

      Stopping immune response from damaging the body is a cornerstone in all inflammations and infections. A simple example would be the “fever”, we try to get rid of the fever when it damages the body even it is an immune response to try to get rid of the invading organism by altering body temperature.
      Same concept applies to immmune therapy, it is just to stop the collateral/associated damage of whatever is taking place, being it directly related to EBV or not.

      • Thanks for your response.

        “MD1 is one of my best good looking scientist I have ever seen”. You need to visit Specsavers!

        I’ve heard MD1’s applying to go on next year’s Love Island! Perhaps he isn’t posting much (apart from boring Covid stuff) because he’s down the gym all the time!

        • Sid why do you have to be rude all the time? MD’s posts (Covid or not) are always informative, good kind of subjective and not misleading. MD’s knowledge and personality and Dr. Wafa’s arts are the best things on this blog in my opinion :). And I have to admit I like MD’s hairstyle.

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