Will neurofilament level monitoring replace brain atrophy measurements as the end-organ biomarker of choice? #ResearchSpeak #MSBlog
Neurofilament heavy and light chain levels, in the cerebrospinal fluid (CSF) and peripheral blood, are a very good biomarker of neuroaxonal damage and loss in MS and other neurodegenerative diseases. Neurofilaments are scaffolding proteins that maintain the structural integrity of axons and nerves. When you damage nerves these proteins are released and can be measured in the fluid around nerve cells, which then drains into the spinal fluid and eventually into the blood. The rate of release and the level is an indicator of the amount of damage that has occurred and/or is ongoing in the brain and spinal cord of pwMS. Raised levels of neurofilament levels are a poor prognostic sign and pwMS who have raised levels will much worse compared to those with normal levels.
The study below on people presenting with CIS, or their first clinical attack, shows that levels in the peripheral blood correlate with the development of brain atrophy, or end-organ damage, and also correlate with EDSS change (disability) over 2 years.
At Barts-MS we are so impressed with the utility of neurofilament levels that we are now using a change in CSF levels over time in a clinical trial of an add-on neuroprotective agent and we have started using NFL measurements in clinical practice. One of our aims is to try and normalise spinal fluid neurofilament levels in pwMS. Knowing that you have normal spinal fluid neurofilament levels helps some pwMS make treatment decisions as well. You may, for example, choose a less risky treatment if you neurofilament levels are low.
| green = neurofilaments |
Kuhle et al. Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology. 2017 Feb 1. pii: 10.1212/WNL.0000000000003653. doi: 10.1212/WNL.0000000000003653.
OBJECTIVE: To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels.
METHODS: Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-β (IFN-β)-1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay.
RESULTS: Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole. Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both).
CONCLUSIONS: Our findings support the potential value of serum NfL as a marker of neuroaxonal injury in early multiple sclerosis. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a noninvasive biomarker of the overall consequences of brain damage and ongoing disease activity.
CLINICALTRIALSGOV IDENTIFIER: NCT00501943.
CoI: Dr Gnanapavan and I are co-authors on the paper
Given the importance of NFL, can pwMS request for an LP from their neuro? How common is that they'll approve it?
Yes, we're currently offering NfL testing for clinical use. The neurologist needs to understand the use of the test, they will not request it otherwise. They will also need to speak to their lab so that the sample can be sent. We measure NfL in all of our Barts Health patients and receive external referrals from outside neurologists.
How good is the blood/peripheral NFL as a biomarker as this would be much easier to use in day to day clinical practice?
Ditto this question. Is there any indication how close we are to a blood assay (such as the Quanterix/Simoa one) being rolled out to measure neurofilament levels in either trials or in a clinical setting?
Maybe NDG can answer she's our Simona queen:-)
As MD suggests blood Nf levels can be measured but don't provide the dynamic change that CSF can on a person to person basis. Which is what we want to use it for i.e to predict subclinical disease activity. What is measured in the blood is a pooled result and may be useful as a one off test, especially if you have elevated levels, but not for continuous readings.