Serum neurofilament light chain falls short of the bar

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Is having a blood test version of this test simply a pipe dream I wonder? Will we have to do lumbar punctures to really find out what’s going on in the brain with MS?

These are questions I grapple with on a regular basis in this field, and what complicates matters is that is positive data and negative data on blood NfL predicting disability progression in MS.

This recent publication shows that in a group of natalizumab-treated patients blood neurofilaments reduced by 50% at 1 year of starting treatment (see Figure below). However, when you look at those who progressed or not progressed, there was no predictive capacity for the test.

So what is going on?

My opinion is that blood NfL levels are not sensitive enough to pick up the changes that are taking place at a slow background level in the brain. CSF sampling with lumbar punctures are probably needed for this. Secondly, NfL is highly sensitive for inflammation but may not be reflective of the whole of the neurodegenerative process i.e. entirely the wrong measure to look at neurodegeneration wholly.

Serum NfL levels over time

Abstract

Neurology. 2021 Sep 9;10.1212/WNL.0000000000012752. doi: 10.1212/WNL.0000000000012752. Online ahead of print.

Serum Neurofilament Light Association With Progression in Natalizumab-Treated Patients With Relapsing-Remitting Multiple Sclerosis

Claire Bridel Cyra E Leurs Zoë Ygj van Lierop Zoé LE van Kempen Iris Dekker Harry Am Twaalfhoven Bastiaan Moraal Frederik Barkhof Bernard Mj UitdehaagJoep Killestein Charlotte E Teunissen 

Objective:The objective of this study was to investigate the potential of serum neurofilament light (NfL) to reflect or predict progression mostly independent of acute inflammatory disease activity in patients with relapsing remitting multiple sclerosis (RRMS) treated with natalizumab.

Methods: Patients were selected from a prospective observational cohort study initiated in 2006 at the VU University Medical Center Amsterdam, The Netherlands, including patients with RRMS treated with natalizumab. Selection criteria included an age of 18 years or older and a minimum follow-up of 3 years from natalizumab initiation. Clinical and MRI assessments were performedon a yearly basis, and serum NfL was measured at 5 time-points during the follow-up, including on the day of natalizumab initiation (baseline), 3 months, 1 year and 2 years after natalizumab initiation, and on last follow-up visit. Using general linear regression models, we compared the longitudinal dynamics of NfL between patients with and without confirmed EDSS progression between year 1 visit and last follow-up, and between individuals with and without EDSS+ progression, a composite endpoint including the EDSS, 9 hole peg test and timed 25 foot-walk.

Results: Eighty-nine natalizumab-treated patients with RRMS were included. Median follow-up time was 5.2 years (IQR 4.3-6.7, range 3.0-11.0) after natalizumab initiation, mean age at time of natalizumab initiation was 36.9 (SD: 8.5), and median disease duration was 7.4 years (IQR 3.8-12.1). Between year 1 and the last follow-up, 28/89 (31.5%) individuals showed confirmed EDSS progression. Data for the EDSS+ endpoint was available for 73 out of the 89 patients and 35/73 (47.9%) showed confirmed EDSS+ progression.We observed a significant reduction in NfL levels 3 months after natalizumab initiation, which reached its nadir of close to 50% of baseline levels 1 year after treatment initiation. We found no difference in the longitudinal dynamics of NfL in progressors versus non-progressors. NfL levels at baseline and 1 year after natalizumab initiation did not predict progression at last follow-up.

Discussion: In our cohort of natalizumab-treated patients with RRMS, NfL fails to capture or predict progression that occurs largely independently of clinical or radiological signs of acute focal inflammatory disease activity. Additional biomarkers may thus be needed to monitor progression in these patients.Classification of EvidenceThis study provides Class II evidence that serum NfL levels are not associated with disease progression in natalizumab-treated patients with RRMS.

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Neuro Doc Gnanapavan

6 comments

  • Surely the key is to find what’s driving MS then find a target drug / therapy.

    Then check bio markers, to see if it’s working or not.

    Clearly MS therapy’s aren’t to effective at progression so is there much point in telling people there still progressing?

    • There are two sets of biomarkers: 1) pathway specific (targeted directly by the drug) which gives an indication of how it’s modified 2) bulk biomakers (neurofilaments is an example) which looks at the end effect of a process. Neurofilaments are released during inflammation and during the degenerative process. High-efficacy treatments that impact on inflammation in a big way also impact on the neurodegeneration giving improved outcomes. Doing the test tells you to a large extent how much of this is subclinical inflammation that can still be impacted on by disease modifying treatments, therefore giving favourable outcome on disease progression. Also, unless you understand the factors leading to progression by doing these measurement in an individual patient you don’t know how to treat it or if it can be treates.

    • Unfortunately, they don’t report on their OCB status as LPs were not done. But would have been interesting if they had this data in the natalizumab treated patients.

    • Not at all, the serum test gives you an indication of treatment response, the CSF one will probably have to be done as an indicator of any slow burn neurodegeneration.

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