Neurofilament light and GFAP
What neurofilaments are
Axons keep their shape thanks to an internal skeleton, and neurofilaments are one of its main building blocks. They are made of light, medium and heavy chains. When axons are damaged, neurofilament light chain (NfL) leaks into the spinal fluid and from there, in much smaller amounts, into the blood. For years it could be measured only in spinal fluid. Ultra-sensitive methods such as the single-molecule array (Simoa) made reliable blood measurement possible, and that turned NfL into a practical test.
What raises NfL
Any damage to axons raises NfL: new MS lesions, but also stroke, head injury and many other diseases of the nervous system. It is a marker of damage, not of MS. Levels also rise with age, because the nervous system loses axons slowly throughout life, and they are lower in people with a higher body mass index, partly because the same amount is diluted in a larger blood volume.
For that reason a single number in picograms per millilitre means little on its own. A Swiss and international group built a reference from 10,133 blood samples of 5,390 people without disease of the nervous system. NfL rose exponentially with age, and faster after about 50. From this reference, any result can be turned into a percentile or a z score for a person's age and body mass index.
Age of the person
25
The same concentration can be high at 25 and ordinary at 70. That is why results are given as z scores or percentiles for age and body mass index.
Illustration. Not real reference values.What NfL tells you in MS
In people with MS followed in the Swiss MS cohort, a higher z score meant a higher risk of future relapses, new lesions and disability worsening. A z score above 1.5 tripled the odds of future clinical or MRI activity (odds ratio 3.15), and this held even in people who had no evidence of disease activity at the time. NfL falls when inflammation is brought under control, so it is used in trials as a sign that a medicine is working, and the authors suggest it could be used to compare the effect of medicine classes in practice.
NfL can be raised before MS is diagnosed. In US military personnel with stored blood samples, those who later developed MS already had higher NfL a median of six years before their first symptoms, and the difference grew as onset approached. A later study of the same population found that NfL rose only after infection with the Epstein-Barr virus (lesson 8.2).
GFAP
Glial fibrillary acidic protein (GFAP) comes from astrocytes, the support cells that react to injury and form scars. Where NfL rises most with acute inflammation, GFAP seems to follow slower processes. In the Swiss MS cohort, higher blood GFAP predicted future worsening independent of relapses (PIRA) and added information to NfL. In healthy people, GFAP rose by about 1.5 per cent for each year of age.
Limits
Neither marker diagnoses MS, and an international consensus on the 2024 criteria advises against using NfL for diagnosis, while accepting it may help with prognosis and monitoring. Results differ between laboratory methods, so a result should be read against the reference for the method used. A single raised value can reflect another illness or an injury, and trends over time are more informative than single tests.
Check yourself
What we know
- NfL in blood reflects recent damage to axons from any cause, and rises with age.
- In MS, a high NfL for a person's age predicts future activity, even when other measures look quiet.
- NfL is raised years before the first symptoms of MS, and GFAP adds information about slow progression.
What we don't know
- Whether adjusting treatment based on NfL improves long-term outcomes.
- What a raised GFAP reflects in progressive MS at the cell level.
- How to standardise results across laboratories and assays so that cut-offs travel.
In the research now
Loading current research…
Key terms
- Z score
- How far a result is from the average of healthy people of the same age, in standard units. Zero is average, above 1.5 is high.
- Simoa
- Single-molecule array, an ultra-sensitive laboratory method that made NfL measurable in blood.
- Axon (nerve fibre)
- The long extension of a nerve cell that carries its signal. Losing axons, rather than myelin alone, is thought to cause most lasting disability.
- Astrocyte
- A star-shaped support cell of the brain and spinal cord. In AQP4-positive NMOSD, antibodies target a protein on astrocytes.
- Lesion (plaque)
- An area of damage where myelin has been lost and the tissue scarred.
- Relapse (attack)
- New or worsening symptoms lasting at least 24 hours, without fever or infection to explain them.
- PIRA
- Progression independent of relapse activity: disability that worsens without a relapse to explain it.
- RAW
- Relapse-associated worsening: disability left behind by incomplete recovery from a relapse.
- Neurofilament light (NfL)
- A protein released when nerve fibres are damaged. Blood levels can rise with new inflammation and fall on effective treatment. Other conditions can also affect its level.
- GFAP
- Glial fibrillary acidic protein, released by astrocytes. Studied as a blood marker of slow progression.
- Epstein-Barr virus (EBV)
- A common herpes virus that causes glandular fever. Infection appears to be almost necessary for MS, but most infected people never develop it.
References
- Benkert P, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol 2022.https://doi.org/10.1016/S1474-4422(22)00009-6
- Bjornevik K, et al. Serum neurofilament light chain levels in patients with presymptomatic multiple sclerosis. JAMA Neurol 2020.https://doi.org/10.1001/jamaneurol.2019.3238
- Bjornevik K, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 2022.https://doi.org/10.1126/science.abj8222
- Meier S, et al. Serum glial fibrillary acidic protein compared with neurofilament light chain as a biomarker for disease progression in multiple sclerosis. JAMA Neurol 2023.https://doi.org/10.1001/jamaneurol.2022.5250
- Deisenhammer F, et al. Positive cerebrospinal fluid in the 2024 McDonald criteria for multiple sclerosis. eBioMedicine 2025.https://doi.org/10.1016/j.ebiom.2025.105905
Next · Lesson 3 of 3
OCT and evoked potentials
The eye is the one place where nerve fibres can be seen directly, and the visual pathway is the easiest to time. This lesson explains optical coherence tomography and evoked potentials, and what they reveal about damage elsewhere in the nervous system.
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