Neurofilament light chain brings a blood-based view of brain health to MS and beyond

Summary

• Neurofilament light chain (NfL) is an emerging blood-based biomarker that provides insight into neuronal damage and may help clinicians monitor disease activity in multiple sclerosis (MS) alongside MRI and clinical assessment.
• Validated blood-based NfL assays are now available for clinical laboratories, enabling reliable measurement of brain injury markers without the need for invasive cerebrospinal fluid sampling.
• Evidence suggests NfL levels can support treatment monitoring and clinical decision-making in MS, helping identify ongoing disease activity and assess patient response to therapy.
• Beyond MS, NfL is being investigated across a range of neurological and critical care settings, with ongoing research exploring its potential role in predicting outcomes, guiding treatment, and improving understanding of brain health.

Multiple sclerosis (MS) is one of the most challenging neurological diseases to monitor. Relapses can arrive with little warning, new lesions can form silently between scans, and the therapies that keep disease activity in check are among the most costly in medicine. MRI and clinical examination remain central to care, but interest in MS blood testing is growing as researchers ask whether a simple sample could add complementary insight.

Neurofilament light chain (NfL), a structural protein released when nerve cells are injured, has become one of the most widely studied candidates. With CE-marked blood-based assays now available from several manufacturers, the conversation is shifting from whether NfL can be measured reliably to how results should be interpreted and where the biomarker adds value.

In a recent accredited SelectScience^® webinar, Professor Tobias Sejbæk, a consultant neurologist at Esbjerg University Hospital in Denmark, reviewed the evidence behind NfL, the analytical factors laboratories should weigh, and emerging research into its use in MS and other conditions. His talk focused primarily on the Siemens Healthineers NfL assay, and he disclosed that Siemens Healthineers supports a trial he is leading.

What NfL reveals

Neurofilaments form part of the neuron's cytoskeleton, giving the cell tensile strength and structure. When neurons or axons are damaged, NfL leaks from brain tissue into the cerebrospinal fluid (CSF) and later into the blood, where levels are roughly 50 to 100 times lower than in CSF.

This sensitivity comes with a caveat. "It's also a marker which is not specific regarding the reason for elevation," Sejbæk explained. Head trauma and cardiac arrest can both raise levels. Among the neurofilament subtypes, however, he noted that the light chain "seems to be the most specific regarding CNS damage."

Timing matters as well. He described a Gothenburg study in which elevated NfL in Olympic-level amateur boxers normalized only after a three-month break. "This is not the fastest biomarker, it's not normalizing fast," he observed. Because NfL is partly cleared by the kidneys, impaired kidney function can also raise levels in people without neurological disease.

From CSF to a validated blood test

Moving NfL testing from CSF into blood demanded far greater analytical sensitivity. In Sejbæk's own study of people with MS, who were on average in their 30s, the cutoff separating patients from healthy controls sat only a little above 10.

"In blood you need to go below five to distinguish between sick and not sick," he said.

According to Sejbæk, Siemens Healthineers introduced the first CE-approved assay for use in blood in 2024. He cited a comparison with Simoa, long regarded as the gold standard, showing an R value close to one, adding that "the results you're getting from Atellica from Siemens are very similar to what is being produced in previous studies with the commercially available Quanterix assay."

His laboratory, which has implemented the assay, ran its own evaluation. Refrigerated samples were "pretty stable for days up to two weeks," he reported, while frozen samples achieved "very similar precision at minus 20 and minus 80."

In a comparison of almost 200 samples, the Atellica tended to produce slightly higher results than Simoa, "but really consistently," he said.

For laboratories evaluating NfL, Sejbæk stressed that context is essential.

"We should normalize for age. That's the most important factor. Body mass index, body size matters," he advised, adding that kidney function affects clearance.

Drawing on work from Jens Kuhle's group in Basel, he explained that when a result sits 1.5 standard deviations above a patient's age- and body mass index-adjusted reference, "the risk of having disease activity in MS is elevated with an odds ratio of 3.15."

Rethinking how MS is monitored

Denmark's national MS registry tells a striking story. According to Sejbæk, "93% on a national level are without disease activity on the yearly imaging."

That raises an obvious question. "So, maybe we scan a bit too much in our daily practice," he reflected.

In his view, "we need treatment biomarkers in MS" to guide decisions such as when to switch therapy. His earlier work showed NfL declining significantly after six months of dimethyl fumarate treatment and approaching healthy control levels by 12 months.

Building on this, Sejbæk is leading a randomized trial in 400 patients on moderately effective therapies, measuring NfL quarterly and triggering additional MRI scans when levels rise 1.5 standard deviations above the age- and BMI-adjusted reference.

Sixteen patients have been randomized so far, and the first flagged by elevated NfL showed a new white matter lesion on follow-up imaging.

"The first patient with elevated neurofilaments did actually have disease activity," he said, while cautioning that the trial's outcome remains to be seen.

Because these patients already provide quarterly safety blood samples, the design fits existing routines.

"So, it's not actually additional effort for the patients to have this measured," he explained.

Sejbæk acknowledged limitations as well. "I'm not sure that neurofilaments are predicting progressive MS, since it's a more smoldering and more silent inflammation that's ongoing in that part of the disease," he said, identifying relapsing MS as the current area of use.

Applications beyond MS

As a general marker of axonal injury, NfL is being studied well beyond MS, alongside other neurology biomarkers.

Sejbæk highlighted a German study in which NfL measured 24 hours after cardiac arrest distinguished patients with good and poor outcomes and outperformed established fluid biomarkers. Cutoffs in that study were around 600, far above typical MS values.

"So, the more neurons that are being damaged, the higher levels of neurofilaments," he remarked.

He also shared a liver cirrhosis study from colleagues at his hospital, in which ammonia "was outperformed by neurofilaments regarding sensitivity and specificity" in identifying hepatic encephalopathy, with Z-score cutoffs that, he reported, were "90% sensitive and 90% specific."

In inflammatory demyelinating polyneuropathy, where immunoglobulin therapy costs "like €30,000 to €40,000 per year per patient," his team found that patients with high NfL "were more likely having disease activity" when treatment was tapered.

"So, you shouldn't taper out this treatment in patients with elevated neurofilaments," he concluded.

A troponin for neurology

Returning to a question he posed at the start of the webinar, Sejbæk compared NfL with biomarkers in other specialties and settled on troponin, which reflects damage to heart muscle.

"I think that's actually the closest biomarker to neurofilaments in neurology," he concluded.

He also recalled that his own NfL measured on non-CE-approved assays showed "variations up to 35%, 38% between labs."

With CE-approved blood assays now available, he sees potential in treatment monitoring, screening, and early-phase drug trials, noting that "we cannot do four spinal taps a year, so blood is really needed."

Yet he admitted that, "we as researchers might have also been a bit too conservative in our approach," and called for intervention studies that test NfL-guided decisions against standard practice.

Reliable blood-based NfL testing has opened a new window on neurological disease, and careful interpretation paired with stronger interventional evidence will determine how far it can go.