Researchers have identified a new method that significantly enhances the diagnostic accuracy of amyotrophic lateral sclerosis, or ALS, by combining two distinct proteins found in the blood. This dual-biomarker strategy offers a more reliable and faster path to diagnosis for a complex neurological condition that is notoriously difficult to confirm. The findings address a long-standing challenge in clinical neurology: distinguishing ALS from other neurodegenerative disorders that present with similar symptoms, thereby paving the way for earlier and more precise patient management.
The new approach, developed by a team from the University Hospital Bonn and Alfried Krupp Hospital Essen, leverages the distinct pathologies of ALS by measuring both nerve cell damage and muscle-specific changes through a simple blood test. By pairing a well-known marker of neuroaxonal injury with a classic cardiac biomarker used in an unconventional way, the study provides a powerful diagnostic tool with prognostic value. Analysis showed that the combination of the two markers substantially improves the ability to differentiate ALS from mimic diseases, a critical step that could shorten the diagnostic journey for patients and allow for earlier access to care and clinical trials.
The Enduring Challenge of ALS Diagnosis
Diagnosing ALS has long been a process of elimination, creating significant uncertainty and delays for patients. The disease affects motor neurons, the nerve cells in the brain and spinal cord responsible for voluntary muscle control, leading to progressive muscle weakness, paralysis, and eventually respiratory failure. Currently, a definitive diagnosis relies heavily on clinical examinations, electromyography to assess muscle and nerve function, and neuroimaging to rule out other conditions that can resemble ALS in its early stages. This diagnostic odyssey can be lengthy and fraught with ambiguity, as there has been a scarcity of specific and sensitive biomarkers to confirm the disease with high confidence.
The clinical presentation of ALS can vary widely among individuals, further complicating its identification. Symptoms can begin in the limbs or with speech and swallowing, and the rate of progression differs from person to person. A number of other neurodegenerative diseases can mimic these symptoms, requiring clinicians to carefully exclude them before confirming an ALS diagnosis. This need for a more definitive and easily accessible diagnostic tool has driven the search for reliable biological markers in bodily fluids like blood and cerebrospinal fluid. An ideal biomarker would not only confirm the disease but also provide information about its likely progression, helping to inform care and treatment strategies.
A Novel Combination of Blood Proteins
The recent breakthrough stems from the innovative combination of two specific blood proteins: serum neurofilament light chain (sNfL) and cardiac troponin T (cTnT). While sNfL was already an established, albeit non-specific, marker in the field, the inclusion of cTnT provides a new layer of specificity that greatly enhances diagnostic power. This dual-marker strategy capitalizes on established and routine laboratory methods, making it a practical tool for widespread clinical use.
Understanding Neurofilament Light Chain
Neurofilaments are structural proteins that are essential components of the neuronal cytoskeleton, particularly in the long axons of motor neurons. When these neurons are damaged or die, as occurs in ALS, neurofilaments are released into the cerebrospinal fluid and subsequently into the bloodstream. Measuring the level of neurofilament light chain in the blood has become a reliable indicator of neuroaxonal damage. However, elevated sNfL is not unique to ALS; it is also found in other neurological conditions, including multiple sclerosis, Alzheimer’s disease, and traumatic brain injury. This lack of specificity has limited its utility as a standalone diagnostic marker for ALS, as it can confirm nerve damage but not its specific cause.
An Unconventional Role for Cardiac Troponin T
The most innovative aspect of the new research is its use of cardiac troponin T (cTnT), a protein traditionally used to detect heart muscle injury and diagnose heart attacks. The researchers found that cTnT is also consistently elevated in the blood of ALS patients. Crucially, this elevation is not due to any underlying heart pathology but is instead linked to muscle-specific changes occurring as part of the disease process. The progressive loss of nerve signals to muscles in ALS leads to atrophy and other changes that cause the release of cTnT. By recognizing this non-cardiac source of the protein, the research team identified cTnT as a valuable second marker to be paired with sNfL, significantly improving the ability to single out ALS from other neurodegenerative disorders.
Rigorous Study Validates Dual-Marker Approach
The effectiveness of the combined sNfL and cTnT test was demonstrated in a comprehensive study published in the journal *Annals of Neurology*. The research team conducted a retrospective analysis and validated their findings in a separate, large group of patients, providing strong evidence for the method’s reliability and potential clinical utility.
Study Design and Results
The initial phase of the study involved comparing data from 293 patients with ALS to two control groups: 85 patients with other neurodegenerative diseases that can mimic ALS, and 29 healthy individuals. Using ROC curve analysis, a statistical method for evaluating the accuracy of diagnostic tests, the researchers showed that the combination of sNfL and cTnT was significantly better at distinguishing ALS patients from the other groups than either biomarker was alone. To confirm these promising results, the findings were then validated in an independent cohort consisting of 501 additional ALS patients.
Establishing a New Diagnostic Threshold
A pivotal finding was the identification of an ALS-specific threshold for cTnT that is considerably lower than the one used in cardiology. The study determined a cutoff of 8.35 nanograms per liter (ng/L) for ALS diagnosis, which is well below the established cardiac cutoff of 14 ng/L used to detect heart damage. By using this more sensitive, adjusted threshold, the researchers were able to correctly identify additional ALS patients who would have been missed using the standard cardiac level. This refinement further increased the sensitivity of the diagnostic strategy, showcasing its power to detect the subtle but consistent muscular changes associated with ALS.
From Diagnosis to Prognosis
The study also revealed that the dual-biomarker test provides valuable insights into the future course of the disease, offering prognostic information in addition to a diagnosis. Researchers found that ALS patients who had normal levels of both biomarkers—referred to as “biomarker-negative”—experienced a significantly slower disease progression. In contrast, patients with elevated levels of one or both markers tended to have a more aggressive form of the disease. This finding is a major step forward for personalized medicine in ALS care. The ability to stratify patients into different prognostic groups at the time of diagnosis could help clinicians tailor care plans, manage patient expectations, and better identify suitable candidates for clinical trials based on their predicted disease trajectory.
Clinical Implications and Future Outlook
The development of this dual-biomarker blood test represents a significant advancement with immediate practical implications for the diagnosis and management of ALS. As stated by Dr. Torsten Grehl of the Alfried Krupp Hospital, the ability to reliably and differentiate ALS from other neurological diseases at an early stage is a crucial aspect of everyday clinical practice. Because the test utilizes established and routine laboratory methods, it can be readily integrated into existing healthcare systems without the need for highly specialized or expensive new equipment.
An earlier and more certain diagnosis can have a profound impact on patients and their families, reducing periods of uncertainty and allowing for faster implementation of supportive therapies. It also opens a wider window for potential therapeutic interventions. With several promising treatments for ALS in development, the ability to diagnose patients sooner and enroll them in clinical trials more quickly is more critical than ever. This new diagnostic tool could help accelerate the development of new therapies by ensuring that trial participants are correctly diagnosed and by allowing researchers to track the biological effects of treatments. The findings open new perspectives for a more personalized approach to both diagnosing and treating ALS.