New studies focus on GFAP for tracking progression and the protein bassoon for monitoring synaptic damage in MS. Here, we break down the results and the clinical challenges that remain.
The field of fluid biomarkers in multiple sclerosis (MS) is rapidly evolving, opening new opportunities to capture different aspects of MS pathology. In this Spotlight, we will explore some of the most recent advances with the leading researchers behind the work.
GFAP as a Marker of Disease Progression
A study involving more than 2,300 persons with MS – over 18,000 samples – showed that elevated levels of glial fibrillary acidic protein (GFAP) in serum were associated with a higher risk of developing progression independent of relapse activity (PIRA) [1.] Interestingly, reductions of GFAP levels following treatment were linked to a lower risk of PIRA [1.]
GFAP and PIRA Risk. We discuss these findings with Professor Jens Kuhle of Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital and University of Basel, “We used two large longitudinal cohorts, the Swiss MS Cohort and the EPIC cohort in San Francisco, to explore and independently validate our results. Higher levels of GFAP were associated with an increased risk of both short- and long-term PIRA. In addition, we observed important treatment effects. Each yearly reduction in GFAP levels during the first two years of treatment in two independent groups of patients, one treated with a B-cell-depleting therapy and the second with fingolimod, was associated with a lower risk of developing future PIRA. I think that GFAP levels in blood may well follow neurofilament light chain (NfL) into clinical practice.”
These results were specific to GFAP, with clearly weaker associations for NfL. High NfL levels were, instead, consistently linked to a higher risk of future relapses [1.] While NfL may effectively track acute relapses, GFAP may track progression. Importantly, unlike relapses and lesions, disease progression is inherently difficult to capture and quantify using Expanded Disability Status Scale (EDSS) worsening. This underscores why the observed associations between GFAP and PIRA are particularly important.
The Difficulty of Measuring PIRA. “Capturing progression in MS precisely is a nightmare,” Prof. Jens Kuhle gets straight to the point, “In one cohort, we measured disability using the EDSS and in the EPIC cohort we applied a composite definition of PIRA, based on confirmed worsening in at least one of three clinical tests: EDSS, or a worsening of more than 20% in the 9-Hole Peg Test or Timed 25-Foot Walk Test. But, of course, none of these measures is perfectly sensitive and specific. For example, when assessing the 500-meter walk as part of the EDSS, results can depend on the time of the day, mood, fatigue, daily fluctuations, comorbidities. Furthermore, supervising a 500-meter walk places additional burden on physicians. Consequently, these measurements are far less precise than one might wish. With that in mind, in our clinical practice, we often use both serum NfL and GFAP, which makes complete sense, especially considering our study.”
Synaptic Damage and the Protein Bassoon
The protein Bassoon can be measured in cerebrospinal fluid and serum of people with MS and signals synaptic damage [2.] This research begins in 2019, when researchers of the University Medical Center Hamburg-Eppendorf (UKE), led by Professor Manuel Friese, conduct large-scale molecular screenings on mice with experimental autoimmune encephalomyelitis (EAE) to observe responses to inflammation inside the neuron [3.] Within the bodies of the neurons, they found a toxic accumulation of the synaptic protein Bassoon [3.]
What is the Synaptic Protein Bassoon? We ask Professor Friese, “It is a structural protein located in the presynaptic terminals – where the neuron sends signals. The protein itself was already known. What was not known was that its expression changes during neuroinflammation. It is a very large protein with a propensity to aggregate. These accumulations are deleterious for neurons. They die because of them, as we showed in our animal models.”
The protein Bassoon abnormally accumulates in the bodies of neurons of animals with EAE. When these stressed neurons eventually degenerate, Bassoon is released and makes its way into the cerebrospinal fluid and plasma [2.]
A Marker of Neuronal Stress. “This protein probably remains in the neuronal somata, because it is no longer properly transported to the synapses,” Prof. Friese continues. “We shared these observations from our animal models with Doron Merkler and his team at the University of Geneva, and they confirmed finding the same accumulations in post-mortem brains of people with MS. So, we thought that if it accumulates inside, it might also be released, which could give us an indication of neuronal stress.”
And, indeed, the researchers found a depletion of Bassoon in cortical synapses of animals with EAE. When measured in plasma, Bassoon levels were significantly increased [2.] Similarly, people with MS showed elevated levels of Bassoon in the cerebrospinal fluid and in most serum samples [2.]
Challenges and Future Directions. “The more progressive the disease was, the higher the signals in the serum,” Prof. Friese explains. “Then, we measured Bassoon levels in persons with progressive disease over three years and observed that they did not change over time. A key challenge was that we established and validated an ELISA for Bassoon, but its detection limit was not good enough – the assay could not detect very low concentrations. This also happened with NfL in its early days. Transitioning to high-sensitivity platforms made all the difference for NfL. So, we also tried to bring Bassoon to high-sensitivity platforms, but that approach did not work. Currently, we are exploring a new approach on a different platform to reliably detect lower ranges as well. Right now, we have essentially only caught the tip of the iceberg, meaning we could only capture patients with very high concentrations. It would also be interesting to spread out those who currently test negative and see the full picture. The hope is that Bassoon will give us a higher resolution of what is happening over time. While NfL allows us to detect acute damage, Bassoon could potentially reveal more subtle damage. But these are still early days, and we need to develop this new marker further.”
Written by Stefania de Vito
Special thanks to Prof. Manuel Friese (University of Hamburg) and to Prof. Jens Kuhle (University of Basel) for their insights.
References
[1] Einsiedler M et al. JAMA Neurology 2026.
[2] Woo MS et al. EBioMedicine 2026; 128.
[3] Schattling B et al. Nature Neuroscience 2019; 22(6): 887-896.