Amyotrophic Lateral Sclerosis (ALS) blood test (© luchschenF – stock.adobe.com)
MONTPELLIER, France — French researchers have identified a blood test that could revolutionize how amyotrophic lateral sclerosis (ALS) is diagnosed and monitored. A team from Montpellier has shown that measuring a protein called neurofilament light chain (NfL) in blood can identify ALS with over 80% accuracy, potentially eliminating the need for more invasive testing.
The study, published in March 2025 in Neurology, evaluated four different technologies for measuring NfL and compared them to other potential biomarkers, finding consistent results across the testing methods.
“Having an effective biomarker can be highly valuable—in addition to helping in making the diagnosis, it can help in predicting prognosis, evaluating what stage of the disease people are in, and tracking their progress or their response to treatments,” said study author Dr. Sylvain Lehmann, of the Inserm Hospital and University of Montpellier, in a statement.
ALS, sometimes known as Lou Gehrig’s disease, progressively destroys motor neurons in the brain and spinal cord. As nerve cells die, patients lose control of their muscles, eventually affecting their ability to speak, eat, move, and breathe. Early diagnosis and accurate prognosis are critical, but until now, diagnosing ALS has been difficult and often delayed.
The researchers studied 209 patients—139 with confirmed ALS and 70 with similar symptoms but different diagnoses. These participants had an average age of 66.1 years, with women making up 47.4%. During the 3.5-year follow-up period for ALS patients, 85.5% died, compared to just 7.7% of the control group—highlighting ALS’s rapid progression.
Which ALS Biomarkers Work Best?
The researchers tested four technologies for measuring NfL: Simoa, Ella, Lumipulse, and Elecsys. They also examined two other biomarkers: glial fibrillary acidic protein (GFAP) and phosphorylated tau 181 (pTau181).
NfL clearly outperformed the others. This protein is found in nerve cells, especially in their long fibers. When neurons die—as happens in ALS—NfL leaks into the fluid around the brain and spinal cord and eventually into the bloodstream. Measuring blood NfL levels essentially tells doctors how much nerve damage is occurring.
People with ALS had NfL levels three times higher than those with other conditions. Meanwhile, GFAP (released during brain cell repair) and pTau181 (associated with Alzheimer’s disease) failed to reliably identify ALS.
Life-Changing Accuracy
All four NfL testing platforms accurately diagnosed ALS more than 80% of the time, while correctly ruling out ALS in over 80% of non-ALS cases. The other biomarkers performed poorly, with accuracy rates around 50%.
Even more remarkable was NfL’s ability to predict survival. Researchers identified specific NfL thresholds that separated patients into groups with vastly different outcomes. Patients with lower NfL levels had a 40-50% chance of surviving at least one year, while those with higher levels had virtually no chance of survival over the same period.
The research revealed how individual characteristics influence biomarker levels. NfL and GFAP concentrations increased with age and decreased with higher body mass index (BMI). The team also found that pTau181 levels varied based on where ALS symptoms first appeared, with higher levels in patients whose symptoms began in the lower limbs rather than in speech and swallowing muscles.
The study confirmed that patients whose symptoms begin in the speech and swallowing muscles (bulbar onset) face a worse outlook than those whose symptoms begin in the limbs—with a 53-65% higher risk of death.
“While more research needs to be done to confirm these findings, having better information about prognosis is valuable for people with ALS and their families as well as the doctors who treat them,” Lehmann said.
What This Means for ALS Patients
Currently, diagnosing ALS involves multiple tests, including specialized electrical tests of muscle and nerve function, and sometimes a spinal tap. These procedures can be uncomfortable, time-consuming, and expensive.
Additionally, having reliable biomarkers could improve clinical trials for new ALS treatments. One challenge in developing effective therapies has been the difficulty in objectively measuring disease progression and treatment response. Blood NfL levels could help researchers better assess whether experimental treatments are working.
For people facing ALS, these advances offer hope. While effective treatments remain limited, better diagnostic accuracy and prognostic information can help patients and families prepare for what lies ahead and make informed decisions about care.
Paper Summary
Methodology
The French research team collected blood from 209 patients who initially presented with symptoms suggestive of ALS at the Montpellier ALS center. After definitive diagnosis, these patients were categorized into two groups: 139 with confirmed ALS and 70 with alternative diagnoses. For each patient, the researchers measured NfL levels using four different platforms and also tested two additional biomarkers. They then analyzed the data using various statistical methods to assess diagnostic accuracy, correlation between different testing platforms, and survival prediction value. They also evaluated how factors like age, sex, body mass index, and site of disease onset influenced biomarker levels.
Results
The study found that all four NfL measurement platforms performed consistently well in distinguishing ALS from non-ALS patients, with areas under the curve ranging from 0.889 to 0.912. This means these tests could correctly identify approximately 80-85% of ALS cases while maintaining specificity above 80%. In contrast, pTau181 and GFAP showed poor diagnostic performance. The study also confirmed that patients with bulbar-onset ALS had worse outcomes than those with limb-onset disease. Among demographic factors, age and BMI significantly influenced NfL and GFAP levels, while pTau181 varied based on the site of disease onset.
Limitations
The researchers acknowledge several limitations to their study. First, their work was conducted at a single center with participants primarily from southern France, which may limit generalizability to other populations. The researchers suggest that other investigators should validate their proposed cutoff values in their own patient populations. Second, the study used a subset of patients from a larger cohort based on sample availability, which could introduce selection bias. Third, while follow-up was extensive, some patients (14.5% of the ALS group) were lost to follow-up, potentially affecting survival analyses. Additionally, extended follow-up might reveal additional conversions to ALS in the non-ALS group. The researchers also note that longitudinal NfL data could be valuable, particularly for ALS patients with initial NfL levels below the cutoffs, to track potential increases over time. Finally, the study focused primarily on NfL and did not extensively evaluate other potential biomarkers for ALS, such as phosphorylated neurofilament heavy chain (pNfH), microRNA-206, or chitotriosidase-1.
Discussion and Takeaways
The study demonstrates that serum NfL measurement provides a reliable, non-invasive method for both diagnosing ALS and predicting survival. The consistency across four different measurement platforms is particularly encouraging, suggesting these results are robust and reproducible. The researchers highlight that two of these platforms—Lumipulse and Elecsys—are already clinically accredited and becoming standard practice in many laboratories, facilitating rapid translation to clinical care. For physicians, the prognostic information provided by NfL levels could be particularly valuable, helping to identify patients with more aggressive disease who might need more intensive care or be candidates for experimental treatments. The researchers note that while NfL levels are influenced by age and BMI, the benefit of correcting for these factors may be limited in ALS due to the dramatic increase in NfL levels associated with the disease. They propose specific diagnostic and prognostic cutoff values for each testing platform, which could serve as reference points for clinical implementation. The authors conclude that these findings provide a foundation for wider adoption of serum NfL testing in ALS management, particularly using the clinically accredited Lumipulse and Elecsys platforms, which could significantly improve patient care by enabling earlier diagnosis and more accurate prognosis.
Funding and Disclosures
The study was supported by Fondation pour la Recherche Médicale (FRM) and the AXA mécénat program through the INTERVAL project. The article processing charge was funded by CHU de Montpellier (Montpellier University Hospital). The authors reported no relevant financial disclosures or conflicts of interest that might influence the study results or interpretation. The funding bodies had no role in study design, data collection and analysis, interpretation of results, manuscript preparation, or the decision to submit the paper for publication.
Publication Information
This research was published in the March 2025 issue of Neurology (Volume 104, Issue 6) under the title “Comparative Performances of 4 Serum NfL Assays, pTau181, and GFAP in Patients With Amyotrophic Lateral Sclerosis” by authors Etienne Mondesert, Constance Delaby, Elisa De La Cruz, and colleagues from institutions including Univ Montpellier, CHU Montpellier, INM INSERM in France, Hospital de la Santa Creu i Sant Pau in Spain, and the University Hospital and University of Basel in Switzerland. The article is available as open access under the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), allowing free distribution of the work when properly cited.
