Blood test may improve accuracy and reduce false ALS diagnoses

Adding a blood test that measures nerve damage or a test of brain activity to standard diagnostic criteria may help doctors diagnose amyotrophic lateral sclerosis (ALS) more accurately, a study suggests.

Researchers found that incorporating either blood levels of neurofilament light chain (NfL), a biomarker of nerve cell damage, or a measure of abnormal brain activity into the Gold Coast Criteria improved the framework’s ability to distinguish ALS from conditions that mimic the disease.

“This multimodal approach provides a practical framework for earlier and more definitive diagnosis,” researchers wrote in the study, “Integration of Serum Neurofilament Light Chain and Cortical Dysfunction Improves Diagnostic Accuracy in ALS,” published in Annals of Clinical and Translational Neurology.

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Researchers test biomarkers alongside ALS diagnostic criteria

ALS is a neurodegenerative disorder caused by damage to motor neurons, the specialized nerve cells that control movement. Because no single test can definitively diagnose ALS, doctors rely on a combination of clinical assessments and diagnostic criteria.

One commonly used framework is the Gold Coast Criteria (GCC). Compared with older criteria, the GCC are highly sensitive, meaning they are less likely to miss ALS cases. However, their lower specificity means some people with conditions that resemble ALS may be incorrectly diagnosed.

Here, a team of researchers in Australia explored whether adding certain disease biomarkers to this framework could help improve its diagnostic accuracy. The team specifically evaluated two biomarkers: blood NfL levels and cortical dysfunction, or impaired activity within the cerebral cortex—the outer layer of the brain responsible for functions such as thinking, language, sensory processing, and movement. In this study, researchers focused specifically on the motor cortex, which helps control movement.

To assess cortical dysfunction, researchers used transcranial magnetic stimulation (TMS), a noninvasive technique that delivers magnetic pulses to the brain. Specifically, they measured short-interval intracortical inhibition (SICI), which is often reduced in people with ALS.

The study included 148 people with suspected ALS who underwent GCC assessment, NfL blood testing, and TMS measurements. Final diagnoses were determined through clinical follow-up by experienced neurologists, using an older diagnostic framework called the Awaji criteria as the reference standard. Of the participants, 101 were diagnosed with ALS and 47 with conditions that mimic the disease.

Combined approach reduced false-positive ALS diagnoses

Results showed that participants with ALS had significantly higher NfL levels and lower SICI values. Researchers used cutoff values to identify results considered suggestive of ALS, deriving the NfL cutoff from this study and using a previously established threshold for cortical dysfunction. They then tested a more flexible diagnostic model that combined the GCC with either elevated NfL levels or cortical dysfunction.

When the GCC were used alone, the criteria correctly identified 89% of people with ALS and 89% of those without the disease. However, when elevated NfL levels or cortical dysfunction — defined partly by reduced SICI — were added to the framework, the proportion of correctly identified people with ALS remained high, at 87%, while the proportion of correctly identified people without the disease rose to 98%, substantially reducing the risk of false-positive diagnoses.

A stricter model incorporating all three measures — GCC, NfL, and cortical dysfunction — also achieved 98% specificity, but sensitivity dropped to 58%, meaning more true ALS cases would be missed.

Statistical analysis showed that NfL levels and cortical dysfunction did not correlate with one another, suggesting they reflect different disease processes and may provide complementary information.

The researchers cautioned that the findings are preliminary and require validation in larger studies.

“The diagnostic performance of combined serum NfL and cortical [inhibition] measures should be regarded as promising but preliminary and require confirmation in multicentre cohorts using prespecified diagnostic thresholds,” they wrote.

They also noted several potential limitations that may arise if trying to apply the framework in clinical practice. Participants taking several medications, including some antidepressants and anti-anxiety therapies, were excluded because those drugs can alter brain inhibition, which may limit how well the findings apply to patients using them. Additionally, measuring cortical dysfunction is more complex to implement because it requires TMS equipment and trained specialists.