I am new to the blog and Barts-MS. I am Dr. Ide Smets and I am an ECTRIMS clinical fellow working in the Barts-MS team. My country of origin is Belgium which is famous for having six governments, for having a national dish that is claimed by another country (French Fries) and for going wild about cyclocross (bring it on Chris Froome ;-)). In 2018, I obtained my PhD in biomedical sciences at the Catholic University of Leuven on the topic of multiple sclerosis. Me and my research lab were able to demonstrate how genetic risk factors for multiple sclerosis shape an individual’s immune system, and in particular the notorious B cell pool. In 2019, I completed my training as a general neurologist in University Hospitals Leuven and I decided – after a journey on the Trans-Siberian express – to head off to London to gain additional hands-on experience in one of the top-notch multiple sclerosis centres in the world.
If you are regular readers of this blog you will have heard about neurofilament light chains already.
Some people consider them one of the most promising biomarkers in multiple sclerosis and other neurological diseases. Neurofilaments are important for the three-dimensional structure of neurons and, when neurons die, they are released into the cerebrospinal fluid and blood. By measuring neurofilament levels in the blood we can estimate the damage to somebody’s brain and spinal cord as a result of MS and how fast their brain function is declining as a result of – unfortunately – time (older age = higher neurofilament levels). This would be of great benefit to many people with MS as neurofilaments would not only reflect the visible inflammation (i.e. the bright white spots on your brain MRI) but also the damage accumulating because of (currently) invisible inflammation in your entire brain and spinal cord.
However, prof. Chris Whitty’s famous words are appropriate here: “no test is better than a bad test”. The study of Khalil et al. has namely investigated the levels of blood neurofilament light chain in a large group of healthy individuals. They have shown that neurofilaments not only increase with increasing age but they also go firmly against our ‘straight-line instinct’. This means that we see an acceleration of brain damage in people after 60 years old, with the levels of neurofilaments increasing every year four times as fast as when you are below 60 years old. Khalil and his team have so far only looked at healthy individuals but as cognitive symptoms and brain atrophy are hallmarks of multiple sclerosis it is not inconceivable that this non-linear increase in blood neurofilaments may start even more early in people with multiple sclerosis.
This has huge implications on how to interpret blood neurofilament light levels in people with MS. Would we be satisfied with a one-time measurement of neurofilaments, similar to other biomarkers you might be familiar with such as oligoclonal bands in the cerebrospinal fluid? Or do we need serial measurements over time, similar to for example CRP which the GP will measure every time you present with an infection?
Personally, I think based on this article it has become unlikely that one-time measurements will do the job unless we are satisfied with a bad test of course. The non-linear increase at older ages makes it treacherous to interpret a single time point measurement, and there will always remain reasonable doubt about whether an individual’s value is within the normal or abnormal range. Too many shades of grey! What would be more informative is to track the neurofilament levels as they evolve over time, similar as to what is done with the height and weight of young babies. If the increase of an individual’s neurofilament level is increasing at a rate that we would expect for a given age, we can all sleep on both ears!
Serum neurofilament light levels in normal ageing and their association with morphologic brain changes
Michael Khalil, Lukas Pirpamer, Edith Hofer, Margarete M. Voortman, Christian Barro, David Leppert, Pascal Benkert, Stefan Ropele, Christian Enzinger, Franz Fazekas, Reinhold Schmidt & Jens Kuhle
Nature Communications volume 11, Article number: 812 (2020)
Neurofilament light (NfL) protein is a marker of neuro-axonal damage and can be measured not only in cerebrospinal fluid but also in serum, which allows for repeated assessments. There is still limited knowledge regarding the association of serum NfL (sNfL) with age and subclinical morphologic brain changes and their dynamics in the normal population. We measured sNfL by a single molecule array (Simoa) assay in 335 individuals participating in a population-based cohort study and after a mean follow-up time of 5.9 years (n = 103). Detailed clinical examination, cognitive testing and 3T brain MRI were performed to assess subclinical brain damage. We show that rising and more variable sNfL in individuals >60 years indicate an acceleration of neuronal injury at higher age, which may be driven by subclinical comorbid pathologies. This is supported by a close association of sNfL with brain volume changes in a cross-sectional and especially longitudinal manner.