Conversations on Biomarker Use in Multiple Sclerosis Remyelination Research

Ahmed Abdelhak, MD

(Credit: UCSF)

Emerging serum and imaging biomarkers are currently aiming to enhance the ability to monitor remyelination in multiple sclerosis (MS). For example, serum neurofilament light chain (NfL) has emerged as a promising biomarker, reflecting neuroaxonal damage and correlating with disease activity and progression. Recent research has shown that elevated serum NfL levels were associated with an increased risk of disability and brain atrophy. Additionally, other serum proteins are being investigated for their roles in neuroinflammation and could contribute to a more complete picture of disease activity in MS.^1,2

Advancements in imaging techniques, particularly MRI, have assisted with the facilitation of identifying remyelinated lesions in vivo.³ Additionally, quantitative susceptibility mapping and myelin water fraction (MWF) imaging have shown promise in distinguishing remyelinated from demyelinated lesions.⁴ These imaging biomarkers, when combined with serum markers, may provide a more comprehensive assessment of remyelination and disease progression for MS. Thus, ongoing research aims to validate these biomarkers and ultimately, integrate them into clinical practice to enhance personalized treatment strategies for patients with MS.

At the 2025 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 28-31, in Phoenix, Arizona, MS expert Ahmed Abdelhak, MD, sat down with NeurologyLive^® to discuss recent advances in biomarkers, such as NFL, that may guide remyelination in MS, based on his presentation given at the meeting.⁵ Abdelhak, assistant professor of neurology at the UCSF, also discussed promising imaging modalities and stressed the need for multimodal biomarker integration in clinical trials. The conversation underscored the broader goal of tailoring therapies based on individual serum proteomic profiles and mechanistic markers to enhance clinical outcomes in MS care.

NeurologyLive: How might emerging serum and imaging biomarkers change the way clinicians monitor remyelination in patients with MS?

Ahmed Abdelhak, MD: That’s such an important question. And as you said, it’s a very exciting topic. You could’ve seen from the other talks in the session that there is immense progress in this field. We are finally starting to see new drugs showing efficacy in inducing remyelination in our patients, which is very important for functional recovery and long-term neuroprotection.

One of the main challenges we’ve been having so far is finding better and more specific ways to monitor outcomes in those trials. One of the things that is very well established—and the group at UCSF, led by Eric Greene, PhD, did immense work on to validate—is visual evoked potential. There is amazing work from Christian Cordano MD, PhD, from our lab, who demonstrated in a very nice way that remyelination really results in changes in visual evoked potential.

So far, this has been integrated into all clinical trials related to remyelination, but we’ve been missing a lot of other markers. Visual evoked potential shows you remyelination only in the visual tract and has some noise at the center level. So one of the main aims, and one of the areas where the field is very interested, is in finding biomarkers that are accessible for many centers and that can be used in many of the upcoming remyelination trials.

Some of those biomarkers originate from serum, and there are also very interesting imaging markers. What we’ve been working on, for example, is trying to study the blood we’ve collected from participants in those remyelination trials in great depth, to find which proteins in the blood change following remyelination. For example, we found that a protein all neurologists are now aware of—NFL—is affected by changes in myelin integrity in this context. In fact, we saw that when you induce remyelination in people with MS, their NFL levels go down.

We did extensive validation of that in animal models and in other cohorts of people with MS. I think we demonstrated in a robust way that if you cause demyelination, NFL levels will go up, and if you remyelinate the axons, NFL levels will be lower. However, as I stressed during the talk, you need the right context to study NFL as a remyelination marker. NFL is heavily influenced by the levels of inflammation we see in our patients—any MS relapses or MRI activity are really impactful. So, in clinical studies looking for remyelination, where you have a very stable patient population, you can use NFL in that context.

In another part of the talk, we also showed new discovery approaches that, by looking at broad proteomic changes in the serum, helped us identify potentially a whole new set of possible remyelination markers. We are now trying to validate these at the tissue level in animal models and in different MS cohorts to define their real clinical context of use.

On the other hand, we have those very promising imaging markers, which have some advantages and disadvantages compared with fluid biomarkers. For example, what we understand from most of the MRI sequences being used now to monitor remyelination is that they might not necessarily have ultimate specificity to reflect only changes happening in myelin. They also reflect changes in axonal integrity and axonal structure, which is one of the limitations.

But on the other hand, you can really use MRI to explore remyelination happening in certain regions in the brain—for example, in the corpus callosum with MWF, or in MS lesions using sequences like MTR. So, I don’t think there’s one optimal marker. Putting all of them together is very important for the next stage of remyelination trials.

What are the most promising biomarkers currently being investigated, and how close are they to routine clinical use?

This is a very exciting field. We have so many possible new markers. I didn’t disclose most of them during the talk, but we talked about NFL in detail. If you look at this panel of markers, you’ll see how extensive the process is of bringing a biomarker from research into the clinical setting.

For example, with NfL, where we have most of data in the field of MS regarding a soluble body fluid marker, we are very close to getting it into the clinic. What we’ve been waiting on is an FDA-approved assay and instrument to run those tests. But we already know a lot about how to use NfL and what an NfL value means in an patient with MS, with our work especially in the context of remyelination.

For other biomarkers, they are at different stages. Some have well-functioning assays but still need further validation to define their clinical context of use. Others are at a very early stage of discovery and assay development. So I’d say we have biomarkers at almost all different stages—some are very close to clinical use, while others still definitely need more work.

The same applies to MRI. It’s probably easier since we’re using clinically available MRI scans, so that part doesn’t need extra validation. But what we do need to validate is what those sequences are actually showing at the tissue level—are they really reflecting what we are expecting? Are they delivering the outcomes we want? If not, there may be a need to develop even more specific sequences. I know this is a topic many groups are actively working on, and there’s a lot of excitement around it as well.

How might these biomarkers help guide treatment decisions or personalize remyelination strategies in practice?

This is actually the topic I’m most focused on now. The beauty of the wide panel of biomarkers we have is that we’re not only looking at the ultimate tissue change—like with NFL, where you see tissue injury—but also at many mechanistic markers and proteins that reflect every individual’s disease state and story.

For example, with the data we showed from the ReBUILD trial (NCT02040298) conducted by Greene, we saw that patients responded to clemastine fumarate in different ways. Some improved a lot, and some improved modestly. Clinically, these patients were quite similar in age and stability. Just looking at the broader clinical picture, you wouldn’t necessarily find a reason why they responded differently. But if you look at their serum proteome, the group that responded very well had a different signature in their blood compared with the group that didn’t respond optimally.

I think that’s really where we want to go with biomarkers in the future—to dissect the disease population and give each group the treatment that works best for them. It’s a long journey, but the fact that we finally have tools that make this possible makes this a very exciting decade for biomarker research.

Any final thoughts you’d like to share on your presentation at CMSC 2025?

I would definitely recommend, as I mentioned in the talk, not to rely on only one biomarker as an outcome parameter in remyelination clinical trials. Let’s leverage the different tools we now have. Let’s find out whether our remyelinating drug really induces functional electrophysiological recovery.

Let’s find out whether it’s really protecting axons. Let’s see where in the brain the changes are happening. And let’s study each patient’s signature related to their remyelination process. I think by leveraging all these tools together, we are getting very close to bringing one of these remyelinating drugs into the clinical setting.

Click here for more coverage of CMSC 2025.

REFERENCES
1. Chitnis T, Qureshi F, Gehman VM, et al. Inflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis. Nat Commun. 2024;15(1):4297. Published 2024 May 20. doi:10.1038/s41467-024-48602-9
2. Pogoda-Wesołowska A, Dziedzic A, Maciak K, Stȩpień A, Dziaduch M, Saluk J. Neurodegeneration and its potential markers in the diagnosing of secondary progressive multiple sclerosis. A review. Front Mol Neurosci. 2023;16:1210091. Published 2023 Sep 12. doi:10.3389/fnmol.2023.1210091
3. Kuhlmann T, Antel J. Multiple sclerosis: 2023 update. Free Neuropathol. 2023;4:3. Published 2023 Mar 9. doi:10.17879/freeneuropathology-2023-4675
4. Rahmanzadeh R, Galbusera R, Lu PJ, et al. A New Advanced MRI Biomarker for Remyelinated Lesions in Multiple Sclerosis. Ann Neurol. 2022;92(3):486-502. doi:10.1002/ana.26441
5. Abdelhak A. Emerging Serum and Imaging Biomarkers to Monitor Remyelination in MS. Presented at: 2025 CMSC Annual Meeting; May 28-31; Phoenix, AZ. Promoting Remyelination in MS.