Barts-MS rose-tinted-odometer: ★★★★★ (Vermillion Monday code #E34234)
There are very few what I call really deep-thinkers in MS research and Danny Reich is one of them. This paper from his group is so simple in its inception and execution; it is a fine example of seeing the woods for the trees. They use a relatively simple MRI technique to interrogate MS lesions to classify them as being remyelinated, demyelinated or mixed.
Using an MRI sequence they classify MS brains lesions as being “long-T1,” “short-T1,” and “mixed-T1”, which correspond to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively. Neat? You bet it is neat. Demyelination, rather than axon loss, dominantly contributed to initial T1 prolongation, which is a metric from the TI relaxation time* on imaging.
*T1 is the so-called longitudinal relaxation time and is the time constant that determines the rate at which excited protons return to equilibrium. It is a measure of the time taken for spinning protons to realign with the external magnetic field.
Short-T1 or remyelinated lesions were most common in the deep white matter, whereas long-T1/demyelinated and mixed-T1/demyelinated-remyelinated lesions were more common in lesions next to the cortex (juxtacortical) and ventricles (periventricular) and were much more likely to have paramagnetic or iron rims suggesting chronic inflammation. The latter are the so-called slowly expanding lesions that are one of the drivers of smouldering MS.
Please note older age at the time of lesion formation meant less remyelination, which is another reminder that as you get older your recovery mechanisms fail.
The question is whether or not this simple technique can be used as an outcome measure in trials and/or to profile pwMS for remyelination studies. There is little reason to load remyelination trials with patients who are not going to be able to respond to remyelination treatments. What about using this technique as a prognostic tool? Is there a biological reason, apart from age, why some pwMS remyelinate and others don’t?
Could this technique be used to supplement evoked potentials to assess whether or not a condition is demyelinating, i.e. as an aid to help make a diagnosis of MS?
You know a paper is good when it leaves you asking more questions than it answers.
Kolb et al. 7T MRI Differetiates Remyelinated from Demyelinated Multiple Sclerosis Lesions. Ann Neurol. 2021 Aug 14.
Objective: To noninvasively assess myelin status in chronic white matter lesions of multiple sclerosis (MS), we developed and evaluated a simple classification scheme based on T1 relaxation time maps derived from 7-tesla postmortem and in vivo MRI.
Methods: Using the MP2RAGE MRI sequence, we classified 36 lesions from 4 postmortem MS brains as “long-T1,” “short-T1,” and “mixed-T1” by visual comparison to neocortex. Within these groups, we compared T1 times to histologically derived measures of myelin and axons. We performed similar analysis of 235 chronic lesions with known date of onset in 25 MS cases in vivo and in a validation cohort of 222 lesions from 66 MS cases, investigating associations with clinical and radiological outcomes.
Results: Postmortem, lesions classified qualitatively as long-T1, short-T1, and mixed-T1 corresponded to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively (p ≤ 0.001). Demyelination (rather than axon loss) dominantly contributed to initial T1 prolongation. We observed lesions with similar characteristics in vivo, allowing manual classification with substantial interrater and excellent intrarater reliability. Short-T1 lesions were most common in the deep white matter, whereas long-T1 and mixed-T1 lesions were prevalent in the juxtacortical and periventricular white matter (p = 0.02) and were much more likely to have paramagnetic rims suggesting chronic inflammation (p < 0.001). Older age at the time of lesion formation portended less remyelination (p = 0.007).
Interpretation: 7-tesla T1 mapping with MP2RAGE, a clinically available MRI method, allows qualitative and quantitative classification of chronic MS lesions according to myelin content, rendering straightforward the tracking of lesional myelination changes over time.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.