1 sign of ALS may be detected up to 15 years before diagnosis
Scientists says blood tests for nerve damage marker may aid in early IDs
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- Elevated blood levels of a marker of nerve damage known as NfL can be detected up to 15 years before an ALS diagnosis, a study found.
- The researchers say early detection using blood tests may help identify presymptomatic biological changes much sooner.
- Still, the team says population-wide screening is considered premature due to the marker's only moderate accuracy.
Blood tests measuring levels of neurofilament light chain (NfL), a biomarker of nerve damage, may help identify people who eventually develop amyotrophic lateral sclerosis (ALS) more than a decade in advance, according to a new study.
Elevated levels of NfL — a protein that provides structural support to nerve fibers — were detected in the bloodstream of patients as early as 15 years before an ALS diagnosis, the researchers noted. Further, the difference in this protein’s levels between individuals who went on to develop the progressive rare disease and people who did not grew larger closer to the time of diagnosis, the team noted.
“NfL elevation [in the blood] may occur significantly earlier than previously reported, indicating a much longer ALS prodrome,” or time before symptoms manifest, the researchers wrote. Per the team, these findings suggest “a substantially longer presymptomatic phase … than generally appreciated.”
The scientists added: “Assuming other biomarker changes may also occur earlier, this raises the possibility of identifying at-risk individuals early that could benefit … clinical trials and prevention efforts.”
Generating such data may also help in epidemiologic analyses, used to study how often diseases occur in groups of people and why, the researchers noted.
Titled “Associations Between Prediagnosis Plasma Neurofilament Light Polypeptide and Amyotrophic Lateral Sclerosis Risk in the Danish EPIC Cohort,” the study was published in the Annals of Neurology.
In ALS, motor neurons — the nerve cells that control voluntary muscle movement — degenerate, leading to muscle weakness and muscle wasting, or atrophy. Most people with the condition ultimately develop respiratory failure.
Doctors diagnose ALS mainly through clinical assessment and neurological examination. However, there’s an average diagnostic delay of 13 months between symptom onset and diagnosis for patients.
According to the researchers, because ALS can be difficult to distinguish from other neurological disorders that affect motor neurons, there is an urgent need for biomarkers to identify the condition as early as possible, even before symptom onset.
Tracking protein levels up to 23 years before ALS diagnosis
NfL essentially serves as part of the internal scaffolding that gives nerve fibers their shape and strength. After a nerve injury, it’s released into the bloodstream and the cerebrospinal fluid, which is the liquid surrounding the brain and spinal cord.
Previous studies have consistently reported higher NfL levels in people with ALS — but those studies collected samples after diagnosis. While some studies have detected elevated NfL before ALS diagnosis, few have collected samples more than 10 years prior, the researchers noted.
That gap led a team from the U.S., Denmark, and Switzerland to assess NfL blood levels for as long as 23 years before an ALS diagnosis.
Their study compared 165 people taking part in the Danish EPIC study — designed to investigate associations between dietary habits, lifestyle, and cancer development — who were diagnosed with ALS and 332 people without ALS, who served as controls. A total of 61% of those with ALS were men; the study matched the two groups by birth year and sex. Among those with ALS, the mean age at diagnosis was 70. The median time between blood collection and diagnosis was 14.1 years, with a maximum of 23 years.
Across all patients and controls, the results showed 1.6 times greater odds of developing ALS among those with elevated NfL, after accounting for smoking and body mass index, a proxy measure of body fat. The findings did not differ by sex.
The researchers then examined the time between blood collection and diagnosis. The team found that the odds of ALS were 3.8 times higher when samples with elevated NfL were collected less than five years before diagnosis, and 1.7 times higher for samples collected five to 14.6 years before diagnosis.
For samples collected beyond 14.6 years, the risk of ALS was 1.3 times higher, but the difference didn’t reach statistical significance, meaning it could have occurred by chance.
The results were similar using the area under the curve, which measures how well NfL distinguished future ALS cases from controls. An AUC of 1.0 represents perfect discrimination. The AUC was 0.78, 0.63, and 0.55 for samples collected less than five years, between five and 14.6 years, and more than 14.6 years before diagnosis, respectively.
Population-wide screening ‘likely premature,’ per researchers
The team also compared NfL levels in each case with the mean of the two matched controls. These results showed that NfL levels were similar in patients and controls until about 16 years before diagnosis, according to the team.
Most participants, either patients or controls, had no recorded diagnosis of another neurological condition (90.9% vs. 94.5%), the data showed.
Among those who did have another neurological condition, Parkinson’s disease was the most frequent, found in 3.6% of ALS patients and 2.1% of controls. Four of the six Parkinson’s diagnoses in ALS cases occurred less than one year from the ALS diagnosis, suggesting an initial misdiagnosis of Parkinson’s, the researchers noted. Removing participants with a record of another neurological condition did not change the results, the team noted.
Our findings extend previous evidence by demonstrating that [blood NfL] levels are elevated even earlier than previously appreciated — up to 15 years — before the clinical diagnosis of ALS.
Overall, per the researchers, the “findings suggest that ALS-related biological changes are occurring much earlier than generally appreciated.”
However, because NfL is a general marker of nerve damage and the AUC is moderate, the team wrote that “population-wide screening for NfL levels as an ALS screen is likely premature.” The researchers called for additional prospective studies to “directly compare prediagnostic NfL trajectories” across ALS and other neurodegenerative diseases to better assess the protein’s ability to specifically indicate ALS.
Still, the team noted: “Our findings extend previous evidence by demonstrating that [blood NfL] levels are elevated even earlier than previously appreciated — up to 15 years — before the clinical diagnosis of ALS.”
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