In the June 2 Neurology, researchers make a strong case that blood levels of neurofilament, a protein released from motor neuron axons, forecast how quickly amyotrophic lateral sclerosis will progress. The marker might help clinicians identify suitable participants for clinical trials, and quickly determine whether they respond to treatment, said senior author Martin Turner of the University of Oxford in the U.K.

Bad-News Biomarker

High levels of neurofilament in blood or cerebrospinal fluid suggest a fast-moving version of ALS. Here, antibody staining (brown) for the heavy subunit of neurofilament in the human cerebellum highlights the axons of basket cells surrounding Purkinje cells. [Image courtesy of EnCor Biotechnology Inc.]

Neurofilaments provide structural support for axons. They are made of three subunits: light, medium, and heavy. When neurons are injured, they leak neurofilament subunits, which can make their way into the cerebrospinal fluid and from there to the bloodstream. Many scientists have investigated the possibility of using leaked neurofilament as a biomarker for neural damage in ALS and other neural conditions (Skillback et al., 2014Scherling et al., 2014McCombe et al., 2015).

In the current study, Turner and co-senior author Andrea Malaspina of Queen Mary’s University, London, addressed a gap in the literature. There is little understanding of how neurofilament levels in patients change over time, though one study looked at the heavy subunit in serial blood tests (McCombe et al., 2015). Turner and colleagues analyzed neurofilament concentrations over time in two ALS cohorts, one at Oxford and one at Queen Mary’s. First author Ching-Hua Lu, of Queen Mary’s, used an electrochemiluminescence assay to detect the light subunit of neurofilament (Gaiottino et al., 2013). They applied this assay to blood, CSF, or both, from 167 people with ALS and 78 healthy controls. Samples were taken at baseline, then every two to six months, for up to 15 months.

People with ALS always had more of the light chain in their CSF than controls did, and blood levels of the protein were nearly as good at distinguishing disease. However, for each person, the neurofilament light chain levels in both blood and CSF remained fairly constant throughout the study.

To correlate neurofilament levels with progression, the researchers tracked symptoms on the standard, 48-point ALS Functional Rating Scale. A decline of 0.5 to 1.0 point per month is considered average. Those who progressed faster had more neurofilament light chain in their blood than those on a slower course. High neurofilament also correlated with shorter survival.

“I think neurofilament light chain is now our leading biomarker candidate,” Turner said. Clinical trialists might see changes to a person’s neurofilament levels in just a couple of months, he speculated, instead of waiting a year or more to determine if a treatment improved survival.

“This study was rigorously conducted and showed clear results,” commented Adam Boxer of the University of California, San Francisco, who was not involved in the work. He called it “strong confirmation” of previous studies suggesting neurofilament as an ALS biomarker (Tortelli et al., 2012). Boxer speculated that having a simple, robust blood test would make it easier for patients to participate in a clinical trial. Instead of traveling to a trial center for extensive analysis a dozen times or more per year, they could have their primary care physician collect a blood sample.

Would neurofilament also be useful to diagnose ALS? Turner and Boxer were less sure. Neurons release neurofilament whenever they are injured, so its presence in the blood may not help distinguish ALS from other neurodegenerative or neurological conditions. To test the diagnostic potential, Turner is currently measuring neurofilament levels in people suspected to have ALS or a mimic condition.—Amber Dance

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  1. The finding that neurofilament light chain (NFL) in the CSF is an independent prognostic marker for ALS is very interesting. This study is important because the authors have used longitudinal data and shown that there is little change over the course of the disease. Although the numbers are small and the study sample atypical, it is difficult to avoid these biases in longitudinal studies involving CSF sampling, and the authors acknowledge that. CSF NFL has more potential as a prognostic than diagnostic marker, unless it can be shown that at an early stage of disease NFL levels can correctly classify ALS mimics as not being ALS.

  2. This paper by Lu et al. has the potential to become a landmark paper in ALS research. Although they have focused on using neurofilament light chain (NfL) in blood as a prognostic marker, they could show — using for the first time a relevant number of prospectively investigated patients — that ALS patients have clearly higher NfL levels in blood compared with controls. Indeed, higher a level of NfL seems to be associated with a worse prognosis, even if it is a bit counterintuitive that NfL does not seem to rise in the follow-up investigations. This certainly has to be further investigated, especially if NfL might be used as inclusion or exclusion criteria for treatment trials.

    In my view, their paper opens up for discussion whether neurofilaments should be included in diagnostic work-up. As there is still an overlap between patients and healthy controls, cerebrospinal fluid might be the better choice for such a differential diagnostic. However, further prospective studies with differential diagnostic-relevant cases must be investigated. Their work also raises the question of whether follow-up measurements in blood might give an objective marker of disease onset in patients at risk.

    Five years ago during a Reisenburg conference a clear roadmap for biomarkers on ALS was formulated. The groups in Oxford and London made a major step forward on this agenda.

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References

Paper Citations

  1. . CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology. 2014 Nov 18;83(21):1945-53. Epub 2014 Oct 22 PubMed.
  2. . Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration. Ann Neurol. 2014 Jan;75(1):116-26. Epub 2014 Jan 2 PubMed.
  3. . Serial measurements of phosphorylated neurofilament-heavy in the serum of subjects with amyotrophic lateral sclerosis. J Neurol Sci. 2015 Jun 15;353(1-2):122-9. Epub 2015 Apr 29 PubMed.
  4. . Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One. 2013;8(9):e75091. PubMed.
  5. . Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression. Eur J Neurol. 2012 Jun 11; PubMed.

Further Reading

Papers

  1. . Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2013 Apr;84(4):467-72. Epub 2012 Oct 31 PubMed.
  2. . pNfH is a promising biomarker for ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Mar;14(2):146-9. PubMed.
  3. . Neurofilament heavy subunit in cerebrospinal fluid: a biomarker of amyotrophic lateral sclerosis?. Amyotroph Lateral Scler. 2011 Mar;12(2):144-7. PubMed.
  4. . Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS. Amyotroph Lateral Scler. 2012 Jan;13(1):1-10. PubMed.

Primary Papers

  1. . Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015 Jun 2;84(22):2247-57. Epub 2015 May 1 PubMed.