What Einstein forgot: Multiple Sclerosis curbs “spacetime”

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.