A dynamic field, where significant development has occurred over the last five years – this is how Professor Stefan Bittner from the Medical University of Mainz in Germany describes fluid biomarkers in multiple sclerosis (MS) during ECTRIMS’ recent webinar. Professor Michael Khalil from the Medical University of Graz in Austria moderated the session.
To date, the most clinically advanced fluid biomarkers are neurofilament light chain (NfL) and glial fibrillary astrocytic protein (GFAP), which serve to monitor in serum neural damage and astrocytic activity, respectively. Additionally, free kappa light chains (fKLC) enable the monitoring of local B cell activity in the cerebrospinal fluid. Professor Bittner discusses the importance of NfL while highlighting several technical considerations. NfL is highly stable, can be measured in serum or plasma, and remains unaffected by freezing. However, it is not suitable as a diagnostic biomarker, as it cannot differentiate between healthy individuals and those with MS. Furthermore, elevated NfL levels are not specific to MS but are observed in various conditions that cause neural damage in the peripheral and central nervous system, such as amyotrophic lateral sclerosis (ALS), Huntington’s Disease (HD) and frontotemporal dementia (FTD). NfL increases also exponentially with age. Therefore, it is important to adjust NfL values according to age especially in older individuals with comorbidities. An increased NfL value during a relapse-free interval suggests a higher likelihood of focal disease activity within the next 1-2 years. When an individual with MS undergoes treatment, NfL values are expected to decrease, as they indeed correlate with the efficacy of the therapy.
Professor Bittner notes that during ECTRIMS 2024 Professor Montalban highlighted fKLC as an appropriate paraclinical test for the diagnosis of MS. kFLC are considered interchangeable with oligoclonal bands (OCBs) and can, therefore, serve as a substitute for OCBs in diagnosing MS. In fact, compared to OCBs, fKLC provide a quantitative measure (rather than qualitative) and are faster to measure, more cost-effective, and independent of the rater. However, standardised cut-off values are still needed.
Professor Ahmed Abdelhak from the University of California San Francisco (UCSF) presented the soluble glial markers in MS. GFAP is present especially in mixed active-inactive MS lesions, brain, and spinal cord white matter. GFAP levels in serum are higher in progressive MS compared to relapsing-remitting MS or other conditions, suggesting that they correlate with disease severity. Blood GFAP is consistently elevated in progressive MS. Furthermore, GFAP concentrations are influenced by age, body mass index (BMI), and sex. Combining the levels of serum GFAP and NfL can predict progression independent of relapse activity (PIRA). In relapsing MS, high levels of GFAP predict PIRA in combination with high levels of NfL. In progressive MS, high levels of GFAP, along with low NfL levels, can predict PIRA. If a treatment is associated with a reduction in GFAP levels, this may indicate a long-term protection against PIRA.
Professor Abdelhak mentions also other promising markers, including Chitinase 1 (CHIT1), which reflect microglial involvement, and Chitinase 3 (CH3L1), which captures both microglia and astrocytes. Both show a promising correlation with disease progression. “We have a lot of glial markers beyond GFAP”, Professor Abdelhak concludes.