Expanding its activities into neuromyelitis optical spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), an international consortium led by the Clinical Neuroimmunology Laboratory is establishing novel biomarkers for these diseases, allowing for a more expedited diagnosis and eventually more timely start of therapy.

Swiss MS Cohort Study (SMSC)

The SMSC is meanwhile in its 12th year of existence providinghigh quality clinical and imaging data, and biofluid samples from more than 13’800 time points for translational medicine research and the definition of novel precision medicine tools. SMSC has become the key resource for clinical and translational research projects at RC2NB, the MS Centre at the University Hospital Basel and within numerous national and international collaborations. More than 40 publications authored or co-authored by the Clinical Neuroimmunology Laboratory from late 2023 and 2024 are based on data obtained in the SMSC.

Biofluid Markers: neurofilament light chain and glial-fibrillary acidic protein

The Clinical Neuroimmunology Laboratory has pioneered in the past years the development of neurofilament light chain (NfL) as the first blood- based biomarker up to clinical applicability for personalised medicine in MS (Benkert et al., Lancet Neurology, 2022; Abdelhak et al., Lancet Neurology, 2023); by November 2024 more than 240.000 NfL measurements have been correlated by researchers and physicians using our web based application for the normative database for adults (https://shiny.dkfbasel.ch/baselnflreference/). We recently launched a similar for use in children and young adults (https://shiny.dkfbasel.ch/baselnflreference-for- kids/).

These tools improve the utility of sNfL levels for MS patients and facilitate the detection of correlations with actual clinical and MRI defined disease activity, response to treatment, as well as their prognostic power for later clinical and MRI outcomes, including therapeutic response. Based on these results, NfL has become a reference measure in individual patient workup, as well as in clinical trialling of MS and other neurological diseases.

However, there was a lack of a biomarker reflecting more specifically the neuro-degenerative aspect of MS usually manifesting clinically as continuous disability accumulation (‘progression’).

This gap has recently been narrowed by the results of our studies of glial-fibrillary acidic protein (GFAP) as a second blood-based biomarker for MS (Swiss National Science Foundation grant 320030_212534, 10.2023- 10.2027). GFAP in blood has a stronger capacity than NfL to prognosticate quantitatively the pace of ‘smouldering MS’ or PIRA (progression independent of relapse activity) (Figure 6) and is a predictor of treatment effects on progressive disease pathology, currently the most important unmet need in MS (Benkert et al., Annals of Neurology 2024).

The longitudinal pattern of serum levels (Figure
7) of these two biomarkers illustrate that they depict different pathophysiological pathways. It is, therefore, likely that the combination of NfL and GFAP becomes a standard measure for the development of drugs specifically targeting progression, as well as for personalised disease management.

These results confirm and expand on a prior study (Meier et al, JAMA Neurology 2023) and demonstrate that a single measurement after one year of therapy start delivers a robust prediction of the future course of disease.

Novel cerebrospinal fluid markers for the differential diagnosis of acute stage NMOSD and MOGAD vs MS

We have recently identified granulocyte activation(GAM) and astrocyte damage (ADM) markers as a novel biomarker set for the differential diagnosis of acute stage neuromyelitis spectrum disorders (NMOSD) and MS (JNNP 2023, figure 8). The detection of anti aquaporin 4 autoantibodies in NMOSD is the diagnostic gold- standard. However, these antibodies score negative in approximately 20% of patients overall and their laboratory turnaround time does not match the need for a seamless start of therapy in acute stages. Further, as GAM are likely effector molecules of acute neural damage in NMOSD, they are the first biomarkers that correlate with the actual degree of disability (Figure 6), unlike the anti-bodies targeting aquaporin-4.

Similarly, GAM also correlated with disability in MOGAD (MSJ 30 (3), pp.1180-1181, 2024 and Neurology 109, 7(Suppl1) P9.004, 2024). Measuring levels of the astrocyte damage markers GFAP and S100B might help to differentiate MOGAD and NMOSD.
Higher levels of these markers were found in NMOSD, an astrocytopathy, than in MOGAD, an oligodendrocytopathy. As a result of these studies, we were able to propose, for the first time, a flow chart of biomarker analysis that allows the reliable differentiation of NMOSD, MOGAD and MS, largely independent of the detection of autoantibodies. Our laboratory leads an international consortium to further validate these findings and establish an easy-to-use assay platform for these biomarkers that can also be applied outside of specialised academic centres, expediting the initiation of adequate therapy.