As a researcher what is my perspetive of communicating atrophy and a person with MS. What do you want?


Atrophy is the loss of brain tissue that is often detected using some MRI scans, and is the balance between loss of brain tissue due to aging and MS and the space filling by scar tissue. This is the underlying cause of accumulting disability.

ProfG has spoken about the “shredder”. I am not so sure this is the way to go, but it is important that people understand that MS is a bad condition such that people can make the best decisions as we should not give the impression that it is not problem. I am not from the Watch and Wait and do the minimum school of Medicine that many people ascribe to. But as I am not a neuro I don’t have to make these decisions.

Communicating the relevance of neurodegeneration and brain atrophy to multiple sclerosis patients: patient, provider and researcher perspectives.

Pennington P, Weinstock-Guttman B, Kolb C, Jakimovski D, Sacca K, Benedict RHB, Eckert S, Stecker M, Lizarraga A, Dwyer MG, Schumacher CB, Bergsland N, Picco P, Bernitsas E, Zabad R, Pardo G, Negroski D, Belkin M, Hojnacki D, Zivadinov R.J Neurol. 2022 Nov 14. doi: 10.1007/s00415-022-11405-3. Online ahead of print. Correction.

Central nervous system (CNS) atrophy provides valuable additional evidence of an ongoing neurodegeneration independent of lesion accrual in persons with multiple sclerosis (PwMS). However, there are limitations for interpretation of CNS volume changes at individual patient-level. Patients are receiving information on the topic of atrophy through various sources, including media, patient support groups and conferences, and discussions with their providers. Whether or not the topic of CNS atrophy should be proactively discussed with PwMS during office appointments is currently controversial.

What do you think. Do you want this to be discussed?..It’s your brain

This commentary/perspective article represents perspectives of PwMS, providers and researchers with recommendations for minimizing confusion and anxiety, and facilitating proactive discussion about brain atrophy, as an upcoming routine measure in evaluating disease progression and treatment response monitoring.

The following recommendations were created based on application of patient’s and provider’s surveys, and various workshops held over a period of 2 years:

(1) PwMS should receive basic information on understanding of brain functional anatomy, and explanation of inflammation and neurodegeneration;

(2) the expertise for atrophy measurements should be characterized as evolving;

(3) quality patient education materials on these topics should be provided;

(4) the need for standardization of MRI exams has to be explained and communicated;

(5) providers should discuss background on volumetric changes, including references to normal aging;

(6) the limitations of brain volume assessments at an individual-level should be explained;

(7) the timing and language used to convey this information should be individualized based on the patient’s background and disease status;

(8) a discussion guide may be a very helpful resource for use by providers/staff to support these discussions;

(9) understanding the role of brain atrophy and other MRI metrics may elicit greater patient satisfaction and acceptance of the value of therapies that have proven efficacy around these outcomes;

(10) the areas that represent possibilities for positive self-management of MS symptoms that foster hope for improvement should be emphasized, and in particular regarding use of physical and mental exercise that build or maintain brain reserve through increased network efficiency, and

(11) an additional time during clinical visits should be allotted to discuss these topics, including creation of specific educational programs.

What do make of this would it be useful?

As a researcher I was originally led to think that neurofilament (a nerve protein released when nerves get damaged) was a marker of progressive neurodegeneration and so could be used in an outcome of progressive MS trials, but we learned the hard way that it is mainly a marker of inflammation induced neurodegeneration. So it is likely to be like a marker of a whole CNS scan. Now this is increasingly become common knowledge and our story is too late to tell.

We could easily see this in the mice…when they had undergone inflammation induced neurodegeneration it was easy for NDG to pick it up in the blood, but when they were undergoing progressive deterioration it was next to impossible to see in the blood.

Gnanapavan S, Grant D, Pryce G, Jackson S, Baker D, Giovannoni G. Neurofilament a biomarker of neurodegeneration in autoimmune encephalomyelitis. Autoimmunity. 2012 Jun;45(4):298-303.

It seems EAE is like MS and measuring neurofilament is an alternative to brain scans and is not the measure for progressive MS I originally thought it was, but it says to me the most damaging aspect of MS is neurofilament and so its presence should not be ignored…………………..

Zondra Revendova K, Starvaggi Cucuzza C, Manouchehrinia A, Khademi M, Bar M, Leppert D, Sandberg E, Ouellette R, Granberg T, Piehl F. Demographic and disease-related factors impact on cerebrospinal fluid neurofilament light chain levels in multiple sclerosis. Brain Behav. 2022:e2873. doi: 10.1002/brb3.2873.

Background: Neurofilament light (NfL) levels reflect inflammatory disease activity in multiple sclerosis (MS), but it is less clear if NfL also can serve as a biomarker for MS progression in treated patients without relapses and focal lesion accrual. In addition, it has not been well established if clinically effective treatment re-establishes an age and sex pattern for cerebrospinal fluid NfL (cNfL) as seen in controls, and to what degree levels are affected by disability level and magnetic resonance imaging (MRI) atrophy metrics.

Methods: We included subjects for whom cNfL levels had been determined as per clinical routine or in clinical research, classified as healthy controls (HCs, n = 89), MS-free disease controls (DCs, n = 251), untreated MS patients (uMS; n = 296), relapse-free treated MS patients (tMS; n = 78), and ProTEct-MS clinical trial participants (pMS; n = 41).

Results: Using linear regression, we found a positive association between cNfL and age, as well as lower concentrations among women, in all groups, except for uMS patients. In contrast, disability level in the entire MS cohort, or T1 and T2 lesion volumes, brain parenchymal fraction, thalamic fraction, and cortical thickness in the pMS trial cohort, did not correlate with cNfL concentrations. Furthermore, the cNfL levels in tMS and pMS groups did not differ.

Conclusions: In participants with MS lacking signs of inflammatory disease activity, disease modulatory therapy reinstates an age and sex cNfL pattern similar to that of control subjects. No significant association was found between cNfL levels and clinical worsening, disability level, or MRI metrics.

Then we have the next monitoring daily activity with a watch and the less you are active the more is the chance of disability progression. We know EDSS and twenty five foot walk are outcomes used to monitor progression so there is a weak, correlation but I guess if it can detect change it may be interesting but the correlations are pretty weak. I suspect it is a bit of a pain….Charging smart watches every day or week is a pain. I have one that I charge every month, Mrs Mouse has one that runs off a battery and so doesn’t need charging and costs alot less that some of the smart watches.

Block VJ, Cheng S, Juwono J, Cuneo R, Kirkish G, Alexander AM, Khan M, Akula A, Caverzasi E, Papinutto N, Stern WA, Pletcher MJ, Marcus GM, Olgin JE, Hauser SL, Gelfand JM, Bove R, Cree BA, Henry RG. Association of daily physical activity with brain volumes and cervical spinal cord areas in multiple sclerosis. Mult Scler. 2022 Dec 27:13524585221143726. Block VJ, Cheng S, Juwono J, Cuneo R, Kirkish G, Alexander AM, Khan M, Akula A, Caverzasi E, Papinutto N, Stern WA, Pletcher MJ, Marcus GM, Olgin JE, Hauser SL, Gelfand JM, Bove R, Cree BA, Henry RG. Association of daily physical activity with brain volumes and cervical spinal cord areas in multiple sclerosis. Mult Scler. 2022 Dec 27:13524585221143726. 

Background: Remote activity monitoring has the potential to evaluate real-world, motor function, and disability at home. The relationships of daily physical activity with spinal cord white matter and gray matter (GM) areas, multiple sclerosis (MS) disability and leg function, are unknown.

Objective: Evaluate the association of structural central nervous system pathology with ambulatory disability.

Methods: Fifty adults with progressive or relapsing MS with motor disability who could walk >2 minutes were assessed using clinician-evaluated, patient-reported outcomes, and quantitative brain and spinal cord magnetic resonance imaging (MRI) measures. A type of smart watch worn on the non-dominant wrist, remotely assessed activity over 30 days.

Results: Mean age was 53.3 years and median Expanded Disability Status Scale (EDSS) was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures. Greater STEPS were significantly correlated with greater C2-C3 spinal cord GM areas (ρ = 0.39, p = 0.04), total cord area (TCA; ρ = 0.35, p = 0.04), and cortical GM volume (ρ = 0.32, p = 0.04).

Conclusion: These results provide preliminary evidence that spinal cord GM area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology.

COI None….I removed the make of the watch,

Disclaimer: These are my views and nobody else

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  • “it is important that people understand that MS is a bad condition such that people can make the best decisions as we should not give the impression that it is not problem”

    The issue with unrelenting neurodegeneration in MS is that there are no current treatments to deal with it – so patients don’t have a decision. Even the most powerful anti-relapse drugs don’t stop the neurodegeneration. I now see many reports of people who have had HSCT who still accrue disability ie the treatment doesn’t stop the neurodegeneration. This was known about years ago – the early Campath / Alemtuzumab trials (early 1990s) covered people classified as SPMS and the drug did not stop the neurodegeneration.

    The fundamental questions which MS researchers across the world need to answer are:

    – is MS (RRMS, SPMS, PPMS) one disease?
    – are relapses setting up neurodegeneration in the future, or is another process driving neurodegeneration and relapses are just the immune systems response?
    – why have previous attempts to stop / slow neurodegeneration failed?

    I know you think that trial design is behind some of the trial failures (trials for progressive MS), but I think there’s a fundamental gap in the knowledge of what is driving the neurodegeneration. Big investments have been made in progressive MS trials (Natalizumab for SPMS), cannaboids (Plymouth trial), MS Smart…… will the Octopus trial or the MS statin trial deliver? Not sure what the huge investment in the MS tissue bank has delivered ie has it identified the drivers of neurodegeneration? Perhaps Sizomus will deliver, or one of the BTK inhibitors? Perhaps an antiviral to tackle EBV will shut down the reaction of the innate immune system? It’s all been too long coming, but then I look at MND and Parkinson’s and the picture isn’t much better.

    c.10 years ago I listened to an MS lecture by Professor Thompson and he said something like “it’s [MS] a bit more complicated than we first thought”. One of the greatest understatements I’ve heard. I think the original view was that addressing relapses would cure MS. Like an onion, every layer unpeeled reveals more complexity and unpleasantness. MS is MND light and on par with Parkinson’s. The term autoimmune disease really doesn’t capture what’s really going on.

    Happy New Year MD.

    • >The issue with unrelenting neurodegeneration in MS is that there are no current treatments to deal with it

      I think this is incorrect. All the current treatments, even interferon beta, slow neurodegeneration, even in people diagnosed with progressive MS. Yes, there is no treatment that completely arrests the disease process (other than maybe alemtuzumab or HSCT when used very early in the course of the disease) but that doesn’t mean we should give patients the impression that there is no point to treatment at all.

    • “The issue with unrelenting neurodegeneration in MS is that there are no current treatments to deal with it – so patients don’t have a decision”.

      I disagree…..if neurioinflammation is a major cause of neurodegeneration, which it is, there is plenty that can be done.

      The point about progression on CAMPATH and HSCT is accepted and well taken but time is also key and the longer you wait the the more likely it is that insidious progression occurs and the vast majority of people that you make your comments on did not take these agents, from diagnosis. In mice some strains have one attack and this is it

      Likewise for the progressive degeneration that are things that can be done and the easiest now is to sign up to a trial.

      “I look at MND and Parkinson’s and the picture isn’t much bette”r……surely it’s worst for MND the choices are limited and for Parkinsons options are symptomati from the same orator.


      !0 years ago……sadly 1-2 years ago I heard and even more bleak outlook

  • Sid,
    Very well put! As a low hanging fruit, I hope that BTKi and metformin will deliver some relief in the short term. Unfortunately, I don’t think that we are close to a full cure in the upcoming years. My hope is that these low hanging trials will be positive and than will be able to be combined with high efficacy rrms drugs like aCD20.
    What are your thoughts 🤔?

  • So I was wrong – it looks as if Rituximab does slow down neuro degeneration / smouldering MS:

    MD – I have a question regarding BTK inhibitors. Which research team’s work identified there potential as an MS therapy? I hadn’t seen any specific research papers, but then out of the blue 4-5 pharma companies seem to be trialling BTK inhibitors for MS.

    Make sure you see in the new year with a pint of your favourite real ale (Bishop’s Finger) while listening to Slade or The Bay City Rollers.

    • I think it was not any MS team, but pharma chasing B cell therapies. Ataciceptand belimumab were busts (because they didnt understand how they were working) and once you have a new idea from targeting B cell cancer, there is then no big mental leap. The spies soon find out what other companies are up to and like sharks they follow the pack. They dont want to miss the party.

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