What Einstein forgot: Multiple Sclerosis curbs “spacetime”

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We all know that time is relentless and cruel. However, do you believe it ticks at the same imperturbable pace for all of Earth’s inhabitants? 

This has been a controversial topic among scientists, and one of Einsteins biggest mindboggles. Newton believed time was absolute “true time”. If the universe was to be frozen, time would tick on regardless (lockdown has taught us this is definitely partially true). Aristotle believed that what we call “time” is simply the measurement of change: if nothing changed, time would not exist. Mischievously, Einstein asserted that both Aristotle and Newton were right.

Einstein claims clock time is an illusion, unless as a special case in his “spacetime” theory of gravity. He predicted that time passes more quickly “high up” than below, nearer to the Earth. So if a man who has lived at sea-level meets his twin who has lived in the mountains, he will find that his sibling is slightly older. Analogously, a clock placed on the floor runs a little more slowly than one on a table. Time runs slower wherever gravity is strongest, and this is because gravity warps “spacetime”. 

Did Einstein forget about something? 

What if the man at sea-level was diagnosed with Multiple Sclerosis. Would MS undo the slowing effect of gravity? 

In other words: Are pwMS living continuously on Mt. Snowdon while their fellow healthy citizens are lodging in the Lake District? 

First of all, it is important to understand that most of the disability in MS is driven by accelerated ageing a.k.a. progression a.k.a. the clock ticking faster than average. Although tempting, and so much easier to grasp, progression is only partially driven by the lesions on your scan that we so eagerly count (Newtonian behaviour of neurologists). Most of the progression results from the decimation of neurons that results in the elusive factor “brain volume loss”. Unfortunately, clinicians do not have a reliable tool to quantify brain volume loss on an individual basis. From data at group level extracted from trials with standardised (and especially lengthy) MRI imaging, we know that accelerated brain volume loss is apparent in pwMS. However, the problem with “brain volume loss” is that it is not visible to the naked eye in the same attractive way as T2 inflammatory lesions are. We cannot just get out our ruler and measure the space between the cortical grooves or the width of the ventricles. Moreover, longitudinal scanning data are necessary with at least 12 month intervals. Similarly, we also don’t see that time is ticking faster at higher altitudes. It requires abstract thinking and believe in science and its measurement tools. 

Cole and colleagues have bundled forces across eight European centres resulting in brain imaging data from 1204 pwMS and 150 healthy controls. Moreover, they had access to a training dataset of 2001 healthy individuals. They used these data to illustrate the concept of a Brain-predicted age-difference or “Brain-PAD score”. Brain-PAD quantifies how much “older” the brain of pwMS at a given age is compared to healthy controls with the same age. Interestingly, this score can be quantified based on datapoints from a single MRI scan. Estimated mean Brain-PAD scores per MS subtype were: clinically isolated syndrome (CIS) +6.7 years, relapsing-remitting +11.9 years, secondary-progressive +13.3 years and primary-progressive +11.2 years. In addition, their analysis indicated that the annual rate of increase in brain-PAD over time correlated with disability increase measured by EDSS and was faster in pwMS/CIS than in healthy controls.

Of note, the mean magnitude of the apparent brain ageing observed in all people with MS (+10.3 years) in this study was greater than what has been reported in dementia (+9 years), epilepsy (+4.5 years), or after a traumatic brain injury (+4.7 years).

Time thus becomes part of a complicated geometry woven together with the geometry of space and the biology of disease. For pwMS, their disease undoes the slowing effect of gravity coming from the earth or the sun. It is undeniable that MS curbs spacetime, and that this needs to be taken into account when deciding on disease-modifying treatment. If your brain has already aged with 6.7 years compared to peers when you are diagnosed with CIS, it implies that pwMS are continuously residing on Mt. Everest, and that future disability should be prevented at all cost. In summary, as prof. G has repeated over and over again: ‘MS Brain Health: Time Matters.

For more insights on time and space, definitely read Carlo Rovelli’s book ‘The Order of Time’. 

Twitter: @SmetsIde

Longitudinal Assessment of Multiple Sclerosis with the Brain-Age Paradigm

James H Cole, Joel Raffel, Tim Friede, Arman Eshaghi, Wallace J Brownlee, Declan Chard, Nicola De Stefano, Christian Enzinger, Lukas Pirpamer, Massimo Filippi, Claudio Gasperini, Maria Assunta Rocca, Alex Rovira, Serena Ruggieri, Jaume Sastre-Garriga, Maria Laura Stromillo, Bernard M J Uitdehaag, Hugo Vrenken, Frederik Barkhof, Richard Nicholas, Olga Ciccarelli, MAGNIMS study group

Ann Neurol 2020 Jul;88(1):93-105

PMID: 32285956, DOI: 10.1002/ana.25746

Abstract

Objective: During the natural course of multiple sclerosis (MS), the brain is exposed to aging as well as disease effects. Brain aging can be modeled statistically; the so-called “brain-age” paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression, and future outcomes.

Methods: In a longitudinal, multicenter sample of 3,565 magnetic resonance imaging (MRI) scans, in 1,204 patients with MS and clinically isolated syndrome (CIS) and 150 healthy controls (mean follow-up time: patients 3.41 years, healthy controls 1.97 years), we measured “brain-predicted age” using T1-weighted MRI. We compared brain-PAD among patients with MS and patients with CIS and healthy controls, and between disease subtypes. Relationships between brain-PAD and Expanded Disability Status Scale (EDSS) were explored.

Results: Patients with MS had markedly higher brain-PAD than healthy controls (mean brain-PAD +10.3 years; 95% confidence interval [CI] = 8.5-12.1] versus 4.3 years; 95% CI = 2.1 to 6.4; p < 0.001). The highest brain-PADs were in secondary-progressive MS (+13.3 years; 95% CI = 11.3-15.3). Brain-PAD at study entry predicted time-to-disability progression (hazard ratio 1.02; 95% CI = 1.01-1.03; p < 0.001); although normalized brain volume was a stronger predictor. Greater annualized brain-PAD increases were associated with greater annualized EDSS score (r = 0.26; p < 0.001).

Interpretation: The brain-age paradigm is sensitive to MS-related atrophy and clinical progression. A higher brain-PAD at baseline was associated with more rapid disability progression and the rate of change in brain-PAD related to worsening disability. Potentially, “brain-age” could be used as a prognostic biomarker in early-stage MS, to track disease progression or stratify patients for clinical trial enrollment.

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Ide Smets

21 comments

Leave a Reply to luis fernando Cancel reply

  • Are their any treatments in the pipeline for neuro restoration. Maybe for other neurological diseases that could cross over to MS treatments?

  • Hi Ide, does that mean if I’ve donated my brain to research, that I probably need to give it to them now, as there’ll be nothing left in old age!

    Jokes aside – the elixir of life could be a hormonal treatment to help support the aging of a person with MS or neurological disease. Along with prevention of the disease progressing too! A big ask – but I know from a women’s point of view, you age so much more when you’re going through the menopause. HRT is something to be explored more for its benefits for women and men – as it helps to have a good supply of all the depleting hormones to support the onslaught of aging!

    Just a thought!

    Take care and all the best,

    Jane

      • For years I was convinced that my as of then undiagnosed MS symptoms were an almost perfect match for low Testosterone (tired, low libido, ED, anxiety, bouts of dysphoria or even depression…). It was almost impossible to have a sensible discussion about it with doctors even though my level were lowish for my age, they just looked at population average…

        Would definitely like to hear about HRT in MS!

  • As a data scientist, I must say this is a very inventive piece of work. An example of good use of machine learning techniques. I wish the code and the system were open-source and we could work with my wife’s neuro in estimating and tracking her PAD. Barts can help with this?

    • Sounds like a great plan. But I think this would only be possible when we would have a large cohort of healthy controls scanned at the MRI scanners used by the Royal London Hospital. Because what I deduct from the paper is that there is a significant interscanner variability that needs to be addressed, and that the coefficients of the model need to be adjusted ‘locally’. However, Barts-MS is in the process of implementing the Icometrix software which is very well known software to track disease progression MS. TBC! You can already have a look at:
      https://icometrix.com/services/icobrain-ms

  • Feels as if the evidence is stacking up – more validity to the efforts ProfG made to have Alem remain a first line treatment. As someone fortunate enough to receive it over the age of fifty and treatment naive, it distresses me to know that others will now have to use other DMTs and thereby experience greater BVL before they will be considered eligible for it.
    I hope, whilst PwMS play the waiting game for the higher efficacy treatments inflicted on them by the current system, that they are doing what they can for themselves – med diet, IF, exercise and Lipoic Acid!

    • Yes, the evidence is stacking up but there is still no comprehensible tool to really bring brain volume loss measurements to the day-to-day clinical practice. That is really what we are lacking and an unmet clinical need. Luckily at bart-MS we have the neurofilament light at CSF as a surrogate, but that requires a lumbar puncture so still not ideal. Anyway, happy to hear you were treated with alemtuzumab. And indeed, never just wait, diet, exercise really make a difference in terms of brain reserve.

  • If I could set off into space at the speed of light and return to find myself in the future, a time when MS is properly treatable, perhaps by way of EBV treatment, and I could leave my PPMS behind… I might have, except that I would not wish to be separated from my partner, my loved ones in time.

    So I would continue on my current path, with love around me, hoping for an effective treatment to come at last, but accepting of my disease and whatever comes.

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