MULTIPLE SCLEROSIS JOURNAL | AUGUST 01, 2018

Khalil M.

Multiple Sclerosis Journal

DOI: https://doi.org/10.1177/1352458518791518

Neuroaxonal damage is the pathological correlate of clinical disease progression in multiple sclerosis (MS). In order to provide optimal patient care and management, it would be of eminent importance to establish a clinical useful tool to monitor and predict such worsening.(1,2) Neurofilaments (Nf), which are specific to neurons and axons, are to date the most promising markers to monitor neuro-axonal damage.(3) Nf belong to intermediate filament proteins and consist of three isotypes, which are a neurofilament light (NfL) chain of 68 kDa, a neurofilament intermediate (NfM) chain of 150 kDa, and a neurofilament heavy (NfH) chain of 190–210 kDa.(1) Evidence for increased Nf levels in MS mainly exists for NfL and NfH, whereas NfM has not been extensively studied so far.(4)

Analysis of Nf levels was so far limited to cerebrospinal fluid (CSF), because detection systems were not sensitive enough to measure the generally lower concentration of Nf in blood samples. As lumbar puncture is a relatively invasive procedure, data from longitudinal analyses are still very scarce. This has now changed with the introduction of a highly sensitive single molecule array (Simoa) technology,(5) allowing reliable detection of blood NfL levels.(6)

Several studies have proven that NfL in CSF and serum are very well correlated to each other, supporting the notion that serum NfL may be used as a blood-derived marker for neuro-axonal damage.(7-9)

There is evidence showing that both CSF and serum Nfs levels are associated with disease activity, physical disability, and magnetic resonance imaging (MRI) changes in MS; however, clinical follow-up time was relatively short in most of these studies.(1,2,7)

In a recent study in 51 MS patients, it has been shown that higher CSF NfH values could prognosticate an unfavourable disease evolution during a follow-up time of 15 years.(3)Another study in 95 MS cases with a median follow-up time of 14 years could demonstrate that elevated CSF NfL levels were predictive of future physical disability.(10) More recently, a larger study in 259 patients (189 with relapsing–remitting MS and 70 with progressive MS) with a clinical follow-up time of median 6.5 years demonstrated that serum NfL was predictive of Expanded Disability Status Scale (EDSS) worsening over time, and higher serum NfL levels were associated with contrast enhancing and new/enlarging lesions seen on MRI. Most notably, higher serum NfL levels were further related to future brain and cervical spinal volume loss in this study.(7)

These are very promising results that support the potential clinical value of Nf measurements in MS. In particular, serum NfL chain levels can be regarded as an easy-to-measure marker of neuro-axonal damage in MS. However, it is not yet clear to which extent comorbidities, such as peripheral nerve neuropathy and others, may affect blood NfL levels, which may be less relevant regarding CSF NfL levels.

In this issue of Multiple Sclerosis Journal, Bhan and colleagues(11) investigated the prognostic role of CSF NfL in 44 newly diagnosed MS patients during a follow-up time of 5 and 10 years. The primary outcome parameter was EDSS progression as defined by an increase of one point or more if EDSS < 6 and 0.5 or more if EDSS ⩾ 6. The main findings were that higher baseline CSF NfL levels were associated with EDSS progression at 5 years (n = 43) and 10 years (n = 37) follow-up, but this was only a trend at 5 years (p = 0.05) and not significant at 10-year (p = 0.28) follow-up. Generalized Estimating Equations (GEE) analysis showed that higher baseline CSF NfL levels predicted a steeper trajectory in EDSS progression during follow-up (p < 0.01). Patients who converted from relapsing–remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS; n = 6) at 5 years had statistically significant higher CSF NfL levels compared to non-converters (p < 0.01).

This is now another important report underscoring the predictive value of NfL levels for the evolution of future disability in MS, but the validity of this study clearly suffers from the relatively low number of patients investigated. Nevertheless, Nfs are currently the most promising markers to indicate neuro-axonal damage in MS and other neurological diseases. The availability of a highly sensitive blood assay now facilitates its use for further research and in clinical practice. However, several steps need to be undertaken in order to confirm the present findings and to further validate this marker for clinical application.(2)

First, Nfs both in CSF and especially in blood should be tested in more detail in phase II and phase III clinical trials investigating the efficacy of new MS drugs.

Second, age-dependent normative values and ranges need to be defined in order to allow evaluation of Nf levels in individual patients. Along these lines, as Nf are not specific for MS, it would be very important to understand how comorbidities may affect Nf levels, which may particularly be relevant for blood Nf levels. In addition, it will be necessary to define the extent to which longitudinal changes of Nf levels in individual patients can be regarded as clinically significant.

Finally, multicentre analytical assay validation is needed to allow standardized and reliable measurements across different centers and to address the above-mentioned points.

Some of these issues are already being addressed in ongoing studies and we may expect further insights on Nf in the very near future.

References

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2.Khalil, M, Teunissen, CE, Otto, M Neurofilaments as promising biomarkers in neurological disorders. Nat Rev Neurol, 2018, accepted article. 

3.Petzold, A. The prognostic value of CSF neurofilaments in multiple sclerosis at 15-year follow-up. J Neurol Neurosurg Psychiatry 2015; 86(12): 1388–1390. 

4.Khalil, M, Salzer, J. CSF neurofilament light: A universal risk biomarker in multiple sclerosis? Neurology 2016; 87(11): 1068–1069. 

5.Rissin, DM, Kan, CW, Campbell, TG. Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 2010; 28(6): 595–599. 

6.Disanto, G, Barro, C, Benkert, P. Serum neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann Neurol 2017; 81(6): 857–870. 

7.Barro, C, Benkert, P, Disanto, G. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. Epub ahead of print 30 may 2018. DOI: 10.1093/brain/awy154. 

8.Kuhle, J, Barro, C, Disanto, G. Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. Mult Scler 2016; 22: 1550–1559. 

9.Piehl, F, Kockum, I, Khademi, M. Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod. Mult Scler 2017; 24: 1046–1054. 

10.Salzer, J, Svenningsson, A, Sundström, P. Neurofilament light as a prognostic marker in multiple sclerosis. Mult Scler 2010; 16(3): 287–292. 

11.Bhan, A, Jacobsen, C, Myhr, K Neurofilaments and 10-year follow up in multiple sclerosis. Mult Scler, 2018; 24: 1301–1307.