Saturday afternoon saw the 25th International Symposium on ALS/MND expand from two to three sessions running in parallel. Times have changed from the early years of the meeting when sessions finished at lunchtime on the second day because there wasn’t enough stuff to talk about! Rather than flitting between three different lecture halls, I opted to immerse myself in the Biomarkers session, especially since the session was being kicked off with presentations from MND Association funded investigators.
For several years, we have been funding the collection of blood and cerebrospinal fluid (CSF) samples in London through the QMUL ALS Biomarker Study. Under the leadership of Dr Andrea Malaspina this resource has grown to become one of the largest collections in the world, encompassing thousands of samples taken from hundreds of patients over the course of their disease.
Through a longstanding collaboration with the Medical Research Council, we have also funded Dr Martin Turner’s BioMOx study. Although it involves fewer participants than the QMUL study, it makes up for this by its sheer complexity, combining blood and CSF collection with multiple types of neuroimaging.
Getting to grips with neurofilaments
The session started with back-to-back presentations from Dr Malaspina and Dr Turner, who have been pooling their expertise and resources to investigate a promising protein biomarker called neurofilament light chain (NfL). Neurofilaments are long, rod-like structures that form part of the internal ‘scaffolding’ of nerve cells (known as the cytoskeleton). They are particularly important in the maintenance of the long thin nerve trunk or ‘axon’, along which electrical nerve impulses are sent. As motor neurons have the longest axons in the body, they also have the highest levels of these proteins of any cell in the body, so if motor neurons are degenerating, it follows that these proteins will appear in the CSF and blood.
Measuring these proteins accurately is not an easy process, because damaged neurofilaments tend to clump together in blood and CSF in the same way that they do so in dying motor neurons (one of the classic pathological ‘hallmarks’ of the disease) so Dr Malaspina and his team have spent several years refining and optimising the technique. He showed data that showed that samples from MND cases from both the Oxford and London collections could be discriminated from non-MND controls, with a sensitivity and specificity of over 95% for CSF samples.
By comparing disease progression with blood NfL levels at different timepoints over the course of two years, the researchers found a clear and consistent correlation, meaning that they may be able to use this technique to predict disease progression and survival, for.
Dr Turner then introduced data from the BioMOx study comparing CSF NfL levels with Magnetic Resonance Imaging (MRI) scans. He showed that NfL levels not only correlated with structural damage to key parts of the brain associated with the disease, but also that the largest changes over time were associated with the highest NfL levels.
The next presentation introduced us to another member of the neurofilament family. Dr Robert Bowser from Arizona presented results of a study which looked at phosphorylated neurofilament heavy chain levels (pNfH) in the CSF and blood of ALS patients, collected from 30 ALS clinics across the USA. By also measuring another protein called complement component 3 (complement C3) which is involved in stimulating the body’s immune responses, he was able to demonstrate a similar level of sensitivity and specificity to Dr Malaspina’s NfL results.
Taken collectively, this novel combination of techniques could prove very useful in speeding up diagnosis, as well as making an important contribution to the design and evaluation of future clinical trials. The work will need to be confirmed, ideally in larger-scale studies, but it gives the research community some clear targets in the search for the elusive ‘fingerprints’ of the disease.
The MND Association are grateful for the support of the Garfield Weston Foundation in funding Dr Malaspina’s project.
