Are we ready for a simple blood test to monitor MS disease activity?
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.
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.
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.
Objective: To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).
Methods: NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.
Results: In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6–32.7) ng/L to 15.7 (IQR 9.6–22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001).
Conclusions: Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.