Neurofilaments are dynamic scaffolds that help to maintain the structure of nerve projections (axons). A widely-held view is that damage to neurons leads to a release of neurofilament components, which leak into the cerebral spinal fluid (CSF) and, subsequently, the bloodstream. In support of this idea, raised neurofilament levels are seen in the CSF of people with a broad range of central nervous system (CNS) conditions in which there is prominent damage to neurons. These include traumatic brain injury, motor neuron disease, and MS.
Are we ready for a simple blood test to monitor MS disease activity?
There is now strong evidence in MS that CSF neurofilament levels are raised compared to people without the disease, are raised following relapse and in association with MRI lesions, and may help to predict, from the onset, how aggressive the disease will be in a particular individual. Interestingly, CSF neurofilament levels also decrease following treatment with highly effective DMTs.
The clinical usefulness of these observations is limited by the fact that getting regular CSF to measure, means regular lumbar punctures. Even with atraumatic needles, LPs are still not pleasant. It would be much nicer for pwMS if we had reliable biomarkers that could be worked out from blood tests.
This is why there has been a big push to study neurofilament levels in the blood. A study published a few months ago demonstrated that blood levels of neurofilament light chain were higher in pwMS vs controls, and were associated with higher EDSS scores, more relapses, more MRI lesions, and had some value in predicting future relapses.
Building on this work, Novakova et al report a fantastic study of 286 pwMS, 45 people with other neurological conditions, and 42 healthy controls. They asked whether blood levels of neurofilament light were useful markers for disease activity and response to treatment.
They found that blood NF-L levels were higher in the pwMS vs the other two groups. Among people with relapsing MS, NF-L levels were higher in those with disease activity vs those without. Blood NF-L levels changed over time with treatment: while there was no change in those who didn’t have any treatment, blood NF-L levels decreased in those started on a DMT and in those who escalated treatment from a low-efficacy to a high-efficacy DMT. People with Gd-enhancing lesions had higher NF-L levels than those who didn’t. Finally, the authors compared CSF and blood NF-L to see which measure was more accurate in predicting whether someone has disease activity or not. While they were both ok predictors (better than a totally random measure) CSF was far more accurate. CSF was much more sensitive (picked up more people with active disease) but blood was more specific (less likely to misidentify people as having active disease when they didn’t). This all implies that blood NF-L levels are associated with disease activity, change with treatment, and so might be clinically useful to help judge whether someone is being treated with a strong enough DMT.
These data are really great and very promising for developing NF-L as a blood biomarker for monitoring disease activity and response to treatment.
I’d make a few comments. First, they compared CSF with blood in people with relapsing MS only, not progressive MS, and so these results may be of limited useful in progressive disease. The reason for doing this is that disease activity – measured in terms of relapses and new Gd-enhancing lesions – is not the best way of monitoring disease activity in progressive disease. It would be nice to see a separate analysis of how CSF and blood NF-L fare in predicting relevant metrics like hand function, timed walk, cognition, and EDSS in people with progressive MS.
Second, NF-L changes substantially as we age, and we don’t fully understand what the ‘normal ranges’ are for different ages. This study corrects for age by using a simple correction. The problem is that the relationship between NF-L and age may not be a straightforward one and so correcting for age is quite challenging.
Third, this study is able to detect blood NF-L because it uses an incredibly sensitive and fancy piece of kit called a ‘Simoa’ which can detect single molecules of NF-L. This is expensive and would not be available for routine clinical use any time soon unfortunately.
Lastly, what’s clear is that not everyone with active MS has a raised NF-L. Monitoring response to treatment or disease activity is probably of most value in people who do have a raised NF-L.
As always, it’d be great to follow these people up for a while longer and see if NF-L can predict future disease activity in this cohort.