Blood NfL levels are impacted by ALS clinical subtype, study finds

Elevated NfL levels linked to faster disease progression in most patients

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Elevated blood levels of neurofilament light chain (NfL), a biomarker of nerve cell damage, are linked to faster disease progression and shorter survival in most people with amyotrophic lateral sclerosis (ALS), a new study found.

However, the team of researchers observed that blood NfL levels among patients differed by the type of nerve cells that are damaged and the initial disease manifestations. Levels were higher in people with typical motor neuron involvement — where nerve cells from the brain and spinal cord both are damaged — and in those first showing so-called bulbar symptoms, such as difficulty eating or speaking.

These findings suggest that the biomarker “needs to be viewed in the context of clinical phenotypes,” or how the disease damages nerve cells and manifests.

“This context is of importance for the correct interpretation of the biomarker in interventional trials and clinical practice,” the researchers wrote.

The study, “Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study,” was published in the European Journal of Neurology.

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Investigating if ALS disease types affect NfL

ALS is a progressive neurodegenerative disease that damages motor neurons, the specialized nerve cells that control voluntary movements. It affects both upper motor neurons, which connect the brain to the spinal cord, and lower motor neurons in the spinal cord and brainstem, which travel down and out to connect to all the muscles in the body.

How the disease manifests, and how fast it progresses, may depend on which motor neurons are most affected. Damage to upper motor neurons usually causes muscle stiffness and clumsiness, whereas damage to lower motor neurons is more frequently marked by muscle weakness, wasting, and twitching.

In recent years, NfL has been used as a disease biomarker to help predict disease progression and survival in people with ALS. However, it’s unclear if distinct disease presentations have a different impact on NfL and whether they should be considered when using the biomarker.

To find out, a team led by researchers in Germany collected data from 2,949 adults with ALS, who had a median age of 64. The patients were recruited at 16 centers in Germany and Austria between 2019 and 2023. More than half, or 58%, were men.

“The results were obtained in the ‘NfL-ALS’ biomarker study, which is funded by the Boris Canessa ALS Foundation,” Thomas Meyer, MD, director of the Center for ALS and Other Motor Neuron Disorders, at Charité University Hospital, in Berlin, and colead author of the study, said in an email to ALS News Today.

Nearly three-quarters of the patients (72%) had typical motor neuron involvement, which is marked by damage to both upper and lower motor neurons. Among the rest, 17% had damage mainly to lower motor neurons, 8% primarily to upper motor neurons, and 3% only in upper motor neurons — a form of the disease called primary lateral sclerosis.

On average, people with typical motor neuron involvement had the highest blood NfL levels (75.7 picograms per mL, or pg/mL) while those with primary lateral sclerosis had the lowest (37.7 pg/mL).

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Highest blood levels of NFL found in bulbar-onset disease patients

When the researchers looked at where the symptoms of ALS had started, they found that more than half of the patients (52%) had limb-onset disease, where muscle weakness first appears in the arms or legs. This was followed by bulbar-onset disease, seen in 27%, which first affects the muscles around the face and throat.

The remaining patients presented with flail-arm onset (11%), which first affects the upper limbs, flail-leg onset (6%), which first affects the lower limbs, and thoracic onset (4%), where the first symptoms usually include breathing difficulties and trunk instability.

People with bulbar-onset disease had, on average, the highest blood levels of NfL (92.7 pg/mL), followed by thoracic onset (74.5 pg/mL). Among the disease onset subtypes, the lowest NfL levels were observed in the flail-arm group (46.4 pg/mL).

The rate of disease progression, on the ALS Functional Rating Scale-Revised (ALSFRS-R), and disease survival were generally associated with NfL levels in all groups, regardless of motor neuron involvement and disease onset. But each disease subtype contributed differently to NfL elevations, the data showed.

For example, compared with people with limb-onset disease, the odds of having higher blood NfL levels were nearly doubled among those with bulbar-onset disease. Meanwhile, in those with thoracic onset, the odds were nearly halved.

“The study showed that the different ALS phenotypes have a strong effect on ALS progression, but also on the NfL value,” Meyer said, adding that, “for example, the bulbar phenotype has a particularly strong influence on the NfL increase.”

Higher blood NfL levels also were less likely to be observed in people with damage mainly to lower motor neurons or with primary lateral sclerosis, for whom the odds were up to five times as low as for people with typical motor neuron involvement. 

People with high blood NfL levels had a significantly lower probability of survival compared with those with intermediate or low blood NfL, suggesting that the biomarker is linked not only to clinical phenotypes but also to disease progression and survival.

The study showed that the different ALS phenotypes have a strong effect on ALS progression. … It is particularly important for the validity of clinical trials that the treatment (with drug) and control group (with placebo) have clinical characteristics that are as similar as possible in order to be able to establish comparability between the two groups.

“These findings come with a two-sided message,” the researchers concluded.

First, they said, blood NfL must be interpreted based on phenotypes for accurate use in clinical trials and treatment. Second, clinical phenotypes are key for predicting disease outcomes.

According to Meyer, “the results of our research show that ALS phenotypes are important as a criterion for the composition of a study group.”

Classifying patients by their disease subtype could ultimately “optimize the validity and efficiency of clinical studies,” Meyer noted.

“It is particularly important for the validity of clinical trials that the treatment (with drug) and control group (with placebo) have clinical characteristics that are as similar as possible in order to be able to establish comparability between the two groups,” Meyer added.