By ECTRIMS Contributing Writer Stefania de Vito
Like roses in the vineyard, biomarkers could play a sentinel function for neurodegenerative diseases. Looking at the roses planted at the beginning of each vine row, the winemaker can spot the presence of a threatening disease and protect the vines before it spreads. By analogy, precision biomarkers could act as an early warning to detect the pathological processes responsible for biological dysfunctions. This could be of paramount importance in heterogeneous diseases like multiple sclerosis (MS). In this case, very sensitive biomarkers could help maximise the information available for monitoring the therapeutic effects or assessing disease progression. Establishing relations between biological dysfunctions and specific changes in certain biomarkers could be crucial for improving clinical practice. Physicians could diagnose MS more rapidly and accurately, monitor disease activity and tailor treatments to individuals.
The great beauty of NfL
Biomarkers in cerebrospinal fluid (CSF) can offer a unique glimpse into ongoing, specific pathological mechanisms of brain diseases. In MS, disease progression appears to be caused by neuro-axonal damage. A major structural component of neurons, axons, and dendrites is the neurofilament protein. The light subunit of the neurofilament protein (NfL) is released into the cerebrospinal fluid upon neuroaxonal injury. Increased concentration of NfL in the cerebrospinal fluid of people with MS correlates with the degree of axonal damage . Furthermore, a pioneering study conducted by Jens Kuhle and colleagues in 2017  showed high correlations between NfL levels in serum and cerebrospinal fluid, and between serum NfL levels and magnetic resonance imaging (MRI) markers of white matter injury.
“The great beauty of NfL is that it is now measurable in serum”, Professor Kuhle told us in a recent interview, “In the future, a simple blood sample could provide precise and specific information about whom to treat with what and when. That would be a significant milestone towards treatment personalisation. Today, NfL is our most advanced, hotshot fluid biomarker for MS. We mainly use age and BMI (body mass index) adjusted NfL levels to monitor the efficacy of MS treatments. At the University of Basel, we are starting a prospective trial (MultiSCRIPT) nested in the Swiss Multiple Sclerosis Cohort-Study (SMSC). We prospectively evaluate serum NfL levels to assess the potential benefit of earlier escalation and safety of treatment de-escalation in people who have been treated for several years, without showing any disease activity. Reducing the treatment for these patients could make a huge difference.”
Serum NfL is easily measured with a precise value. At the University Medical Center Mainz in Germany, Stefan Bittner shares with us another remarkable advantage of this fluid biomarker, “You cannot destroy sNfL. It remains stable in fresh and frozen blood samples, independently of the storage time. And it really seems to work. Highly increased levels of sNfL reflect acute focal lesions development in patients with MS. However, these lesions can also be easily detected with MRI. The added value of already mildly increased sNfL could be to help monitoring the smoldering chronic neurodegenerative process, which is independent from relapses in people with MS”. Professor Bittner and his colleagues conducted a prospective cohort study to assess the potential utility of sNfL for forecasting disability progression. The researchers observed that sNfL measurements could predict relapse-free disability progression in people with MS 6 years later . “The predictive ability of NfL seems to extend to an individual patient level”, Prof Bittner continues, “Therefore, we are now focusing on patients who show no evidence of disease activity over the last year (NEDA3). They have no clinical relapse, no clinical progression, and do not show new lesions on MRI scans over the last year. We estimate that about 5% of NEDA3 patients have a high probability of disability progression in the long run, which can be predicted by sNfL . We have now started a prospective trial specifically focusing on closely monitoring NEDA3 patients with high sNfL levels (NEDA3NfLhigh trial) to see whether sNfL measurement can really resolve subclinical neurodegeneration.”
The development of easily accessible, precision-medicine biomarkers could be crucial to inform early therapeutic decisions.
If we can measure it, we can improve it
Research is focusing on developing personalised diagnostics and therapies. Today, the most widely used method of monitoring disability worsening in MS is the Expanded Disability Status Scale (EDSS). Regrettably, this diagnostic instrument lacks sensitivity and specificity, and quantifies disability worsening and progression with a certain delay. Capturing disease progression early is the biggest unmet need in the MS field. “The MS framework is moving away from the classic categorisation of relapsing and progressive multiple sclerosis. Now we are embracing the idea that not only progression starts very early, but it is also very prevalent in early MS. Thus, it would be crucial to specifically measure progression as early as possible,” Kuhle says. Achieving this goal will likely require combining clinical evaluation with state-of-the-art MRI, fluid, and digital biomarker assessments. All these tools bear the potential to complement each other in both clinical trials and clinical practice. “The interesting interplay between MRI and fluid biomarkers thrives on the differences between these two measurements,” Jens Kuhle continues. “The most advanced MRI sequences provide detailed maps of the dissemination of MS lesions. This topographical information is lost in serum. However, fluid biomarkers may represent a summary measure, an overview on the entire nervous system, and may potentially capture substrates from lesions that have not yet been observed in MRI.”
For example, a recent study headed by Amit Bar-Or  tracked for nine years NfL levels in the blood of more than 2000 patients treated with ocrelizumab, an antibody that depletes B-cells with clinical efficacy in both relapsing and progressive MS. Despite the treatment, a relevant subgroup of patients, especially in the primary progressive population, persistently showed increased levels of NfL. Moreover, blood NfL levels at baseline were prognostic of disease outcomes. High levels of NfL also under ocrelizumab treatment significantly predicted disability worsening or indicated that NfL could help detect insufficient treatment response (also in progressive MS). In the future, such information could have a critical impact on therapy choice for individual cases.
This year, another study  shows the added value of a second promising serum biomarker candidate, GFAP (glial fibrillary acidic protein). GFAP is a structural component of astrocytes, star-shaped brain cells. In this study, serum GFAP elevated levels predicted better than NfL a progression in disability. Furthermore, combining the two measurements of these two biomarkers together yielded an even stronger (4- to 5-fold) risk of future disability progression.
“NfL has the potential to predict progression,” Ahmed Abdelhak told us in a recent interview, “but the effect of GFAP on predicting progression appears to be stronger in most of the published data. GFAP has the promising potential to predict disease progression particularly in progressive MS patients, and probably in relapsing MS patients in absence of activity. NfL is by far our best candidate to monitor treatment response in MS. However, if you want to use a biomarker to predict progression, you may need something besides NfL. And if you are trying to use biomarkers to understand what is happening in the brain, then you need all of them.”
GFAP is currently under extensive examination and does not always score good grades. Maureen van Dam and her co-authors  found that only NfL, and not GFAP levels, could predict cognitive impairment in people with MS. Once more, it was the combination of two markers (i.e. NfL and grey matter volume) to produce the most promising results. A multimodal marker, i.e. the combination of NfL and grey matter volume, could better detect cognitive deficits in MS. Results based on large cohorts will shed important light on the possibility to promote serum GFAP towards the next level, the clinical practice.
Imaging markers and serum biomarkers are tiles of a mosaic, which can be used in combination to depict different aspects of neurodegeneration. Finding the right measurement tools can help design more efficient clinical trials. Biomarker research is crucial for accelerating the development of novel treatment options. Ultimately, tailoring the therapy to meet individual needs is easier if there is the concrete possibility to choose between different treatments. Returning to our initial analogy, it will be essential to plant more roses in the vineyard and cultivate the most promising ones.
Special thanks to Ahmed Abdelhak (University of California San Francisco), Stefan Bittner (University Medical Center Mainz) and Jens Kuhle (University Hospital Basel) for their insightful interviews.
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Learn more about biomarkers and MS at MSMilan2023
This October, be sure to join the following sessions covering this timely topic:
- Hot Topic 9: Biomarkers of Damage and Recovery
- Scientific Session 7 on “Body fluid biomarkers as surrogate of disease activity, progression and treatment response”
- Young Scientific Investigators’ Session 3: Imaging and Non-imaging Biomarkers
- Educational Session 9: Molecular Biomarkers in MS
- Free Communications 1: Imaging Biomarkers
- Free Communications 4: Imaging and Non-imaging Biomarkers
Haven’t registered yet? Sign up here for MSMilan2023.