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Diagnostics: a clue in a blood sample

We are nonetheless approaching a time when it will be possible to improve an individual’s prognosis for MS by means of a blood test. We are searching for a blood marker for active multiple sclerosis: the use of neurofilament light chain protein (NfL).

During an inflammatory attack of the disease, a MRI scan of the brain or spinal cord shows well-defined lesions that have captured the intravenously injected contrast agent. It is the breakdown of the blood-brain barrier caused by the inflammation that enables these active lesions to capture the contrast agent. They may be associated with new clinical signs (a relapse), or appear silently in areas which do not provoke easily identifiable external symptoms.Basically, inflammation destroys the membranes and hence the “super-membrane” that is the myelin sheath. However, in many cases, the inflammation may also break the nerve fibre (axon) inside the sheath. Once the nerve fibre has been “transected”, its protein content may be released into the cerebrospinal fluid, and finally end up in the circulating blood. This is particularly true of neurofilament light chains (NfL), which are specific to axons.

  • Using state-of-the-art techniques 1,000 times more sensitive than those used in the 80s, it is now possible to assay the NfL protein directly in circulating blood. Various studies have shown that the concentration of NfL in the blood is in direct proportion to that observed in cerebrospinal fluid, so that a spinal tap is not required.
  • A recent study published in March 2019 supplies information concerning the considerable potential of systematically assaying NfL in MS patients. It was performed on blood samples taken during two clinical trials on a placebo group or a group treated with interferon, compared with a group treated with fingolimod (Gilenya®). Control subjects were also tested at the same time.
This study yielded five important pieces of information:
  1. the mean concentration of NfL in the blood was almost twice as high before the start of the clinical trial in the MS patients than in the control subjects.
  2. prior to beginning the treatment, the concentration of NfL in the blood was correlated to the total number of lesions observed by MRI and with the number of active lesions that captured the contrast agent.
  3. prior to beginning clinical testing, the concentration of NfL was predictive of this concentration at the end of the study, one or two years later.
  4. a high NfL concentration at the beginning of the study was predictive of a more frequent occurrence of new lesions and new attacks, of more marked cerebral atrophy, and of a more marked  increase in disability.
  5. further to six months of treatment and thereafter, fingolimod reduced the concentration of NfL in the blood.

Of course, this marker is not specific to MS, since in all diseases in which there is degeneration of the nerve fibres, such as amyotrophic lateral sclerosis, cerebral thrombosis, Alzheimer’s, etc., an increase in NfL content can also be observed.

Nevertheless, the fact remains that within the strict framework of MS, such testing, which hopefully will become available within the next two or three years, will make it possible to identify people at risk of developing a progressive and disabling disease, and to identify “good responders” to specific treatments. The NfL blood levels of such good responders should typically return to normal values.

However, before such a test becomes useful, the technique will need to be fine-tuned, its robustness and reproducibility checked, and reference values determined. We are nonetheless approaching a time when it will be possible to improve an individual’s prognosis for MS by means of a blood test.

Prof. Dr. Christian Sindic