Age is a compelling causal argument for MS

A

Fact – autoimmune disorders affect the young.

Fact – the immune system ages with you as does rest of the body.

Fact – MS is an autoimmune disorder.

This week we find yet another study re-iterating the point that the evolution of MS lesions is an age-dependent phenomenon. This time using MRI head scans, in what is arguably one of the largest series published on the topic.

Gadolinium-enhancement (a marker of active MS) declines with increasing age (see Figure below). This plays out in natural history MS cohorts that demonstrate that relapses decrease with age also (in the British Columbia cohort, the rate of relapse dropped by 17% for every five years of follow-up). Concurrently, those with relapsing-remitting MS (RRMS) also tend to have those most active scans.

Figure: Proportion of patients with gadolinium enhancement on cranial MRI by age (left panel) and by disease course (right panel)

If your aim is to achieve the closest thing to a cure in MS – which is freedom of disease activity; it pays to consider the highest tier of targeted immunosupression in this particular cohort of MS.

Abstract

J Neurol. 2020 May 9. doi: 10.1007/s00415-020-09895-0. [Epub ahead of print]

Gadolinium enhancement on cranial MRI in multiple sclerosis is age dependent.

Koch MW, Mostert J, Greenfield J, Liu WQ, Metz L.

BACKGROUND:

Epidemiological, pathological and radiological studies suggest that inflammatory demyelination in MS is an age-dependent process, and that the formation of focal inflammatory demyelinating lesions decreases with age. Gadolinium-enhancing lesions are a biomarker of inflammatory disease activity in MS, but little is known about the relation of age and gadolinium enhancement on cranial MRI scans in people with MS. In this study, we investigated the association of age and other risk factors with gadolinium enhancement on cranial MRI in a retrospective cross-sectional clinical MS cohort.

METHODS:

In a cohort including 1543 people with CIS and MS, we investigated the association of the risk factors age, sex, disease course, immunomodulatory drug (IMD) treatment, and disability with gadolinium enhancement on cranial MRI scans using a binary logistic regression model.

RESULTS:

Age was the most important factor associated with gadolinium enhancement, with the odds of gadolinium enhancement decreasing with advancing age. Participants with CIS had lower odds of gadolinium enhancement (odds ratio of 0.42, 95% confidence interval of 0.24-0.72 compared to RRMS). Sex, disease course and IMD treatment were not significantly associated with gadolinium enhancement in our cohort.

CONCLUSIONS:

Our investigation shows that gadolinium enhancement is strongly associated with age. Since gadolinium enhancement is a marker of inflammatory disease activity, our findings suggest that inflammatory disease activity declines with age, and that IMD treatment may be more beneficial in younger and less useful in older people with MS.

About the author

Neuro Doc Gnanapavan

6 comments

  • And so one might even argue that > 60 years of age (which is without doubt an arbitrary cut-off), DMT therapy is probably useless. But most of us plough on. Regardless of benefit. Should we not stop ?

    Most patients probably have SPMS by that age, if they have had RRMS earlier; cortical atrophy, deep gray matter involvement, B cell follicles in the meningeal layers causing sub-pial damage all contribute to SPMS, presumably and/or not amenable to traditional treatment approaches. Yet, there is a strong push by pharmaceutical companies to tease out ‘treatment options for disability’ associated with SPMS or either strive to halt it or ‘reverse it’. With the breach of BBB being less and less as one ages, perhaps, it comes as no surprise that immunologically senescent cells do not partake in the pathological process and the brain and cord are perhaps being driven by neurodegeneration which begins early and perhaps in parallel with neuroinflammation.

    • This is one way of looking at it. It’s important note that the age cut off for most Phase 3 studies are 55years old. The use immunosuppressants in the older age group becomes an evidence free territory. As cancer rates increase rapidly after midlife, the role of immunosuppression in treating MS in the older population needs to be carefully considered (at least the highly active ones).

  • Thanks for the post.

    “Fact – MS is an autoimmune disorder.“ I was under the impression that this assumption had yet to be proved. For example, if MS is caused by a virus in the CNS, then the immune system is doing it’s job and not turning on itself for the sake of it.

    Are we any nearer to mapping out what this disease is about ie the trigger, processes which drive it, the mechanisms behind neuro-degeneration etc. I’ve had the disease for almost 20 years, but still see terms such autoimmune, neurodegenerative, inflammatory, environmental factors, age, gender, hormones, genetics…. I don’t get any sense as to whether our understanding of the disease is any more advanced than 20 years ago. With all the advances in imaging, computer modelling, gene analysis etc. are we any nearer to better understanding what MS is?

    • So this is where the confusion arises. Different groups work one aspect of the disease leading to a piecemeal presentation. But I don’t think that the autoimmunity is an answered question. There are different triggers to it such as EBV and HERVs but it is more or less the immune response that does the damage. No other factor is more prominent in the research findings. But groups seem to want to reinvent the wheel. The focus should be as you say fixing the neurodegeneration dilemma.

      • Thanks. You’ve perfectly summarised my own assessment.

        “Different groups work one aspect of the disease leading to a piecemeal presentation.“

    • Unproven, but generally accepted theory – MS is an autoimmune condition.
      Fact – 100% of pwMS are infected with EBV in a sample of n=901 in Germany, which is probably generalisable.
      Theory 1 – B cells infected with EBV attack host cells, triggering an immune cascade in the CNS. This is my preferred theory as immune senescence would blunt the immune cascade and fit with this research finding.
      Theory 2 – Oligodendrocytes are collateral damage as the host immune system attacks infected B cells.
      Theory 3 – T cells infected with EBV direct healthy B cells to attack the host.
      Theory 4 – Something else is going on.
      The problem we have is that theories become generally accepted and start getting reported as fact when they are not.

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