Learning to Use Neurofilament Light Clinically

Peter A. Calabresi, MD, the director of neuroimmunology and a professor of neurology at Johns Hopkins University

Peter A. Calabresi, MD

With so much discussion surrounding the clinical validation of neurofilament light as a biomarker for multiple sclerosis (MS), the reason for its attempted validation may be lost to some.

Neurofilament, a nonspecific biomarker of axonal damage in the central nervous system, has emerged in recent years as a leading candidate for the measurement of the efficacy of disease-modifying therapies. As such, researchers have been working to better understand how it should be used and what amounts of it are clinically relevant.

Peter A. Calabresi, MD, the director of neuroimmunology and a professor of neurology at Johns Hopkins University, is one of the physicians working to validate neurofilament in the clinic. At the 2018 meeting of the European Committee for Treatment and Research in Multiple Sclerosis, in Berlin, Germany, he spoke with NeurologyLive about this work. He also provided some insight into what prompted the use of it as a possible biomarker.

NeurologyLive: What brought about the use of neurofilament as a potential biomarker?

Peter Calabresi, MD: If you think about it, a lot of diseases have blood tests. You go to your doctor, and you get blood tested. But in many neurologic diseases, we don't have blood tests because they're basically problems with the brain and spinal cord, in the case of MS. For the most part, we don't think of brain proteins as having access to the bloodstream, but in this case, there is a lot of literature to support the notion that when the brain is being actively damaged, microscopic amounts of neurofilament are released into the bloodstream and can be measured.

The issue is where this stands right now—because some people say, “well is it ready to be a blood test for MS?”—is that we have a technically valid assay through a company called Quanterix and that so that means the assay is sensitive, it's reproducible, it's got a reasonable coefficient of variation, test-retest reproducibility. We know that, biologically, these [neurofilaments] are being released and from the brain and spinal cord from people with MS, but we don't really know how to use it clinically. It needs clinical validation.

What ways are there to clinically validate neurofilament for MS?

One way to do that is to analyze large cohorts and see if they move in the direction you want them to move. So, the people who have elevated levels of the neurofilament, do they end up having more MRI activity over the course of the next year? Or down the road, do they have progression on their EDSS? We're able to show, at the cohort level, some very nice relationships but now the question is: Can we look at individual patients and is there a cut-off level that would predict who might have the likelihood of this happening to them, individually?

If you go to the doctor and give blood, you want to know what the meaning of elevation is. With a lot of blood tests, you have to establish what's normal and what's not normal. We know for many things, like blood counts, that at a certain level you suddenly anemic, but if you’re 0.1 below the normal range, does that mean you're really anemic? Not really. So, we're trying to figure out what is clinically meaningful.

This where all of us who practice neurology, we're looking at this cohort to see if we can inform ourselves as to what would be a level that you would react to, and are these neurofilaments responsive to therapies? These are the kinds of questions that we address.

Transcript edited for clarity.