Blood Test Detects ALS Years Before Symptom Onset

 A blood test that detects proteins unique to amyotrophic lateral sclerosis (ALS) can identify those with disease years before symptoms appear, new research suggests.

"We had always assumed that ALS was a rapid disease that starts 12 to 18 months before symptom onset," study investigator Alexander Pantelyat, MD, associate professor of neurology at the Johns Hopkins University School of Medicine, said in a press release. "But when we look at our findings, we see this has been a process that goes on for a decade or so before the patient ever steps into the doctor's office or clinic."

The study was published on August 19 in Nature Medicine.

'Distinct Molecular Signature' 

A reliable method for diagnosing ALS has been elusive, the researchers noted. Existing biomarkers for ALS rely on a single measurable characteristic, such as neurofilaments, for diagnosis and monitoring disease progression. Finding an accurate biomarker for ALS before symptoms start could aid in patient care, clinical trials, and better understanding the mechanisms of the disease.

What's more, those diagnosed with ALS typically live for 2-4 years after symptoms begin, but these findings suggest the disease may start 10-15 years before symptoms appear.

In a cross-sectional study, researchers enrolled 281 patients with ALS and 258 participants from a healthy control population from the University of Turin and the National Institutes of Health. Plasma samples were taken from patients and participants, and researchers used a proteomics platform to identify proteins specific to ALS from a total of 2886 proteins.

Using machine learning, researchers developed a best-performing model of proteins based on data from a training set of 181 patients with ALS and 172 healthy participants as well as 137 patients with other neurologic diseases. The model was then tested on samples from 48 patients with ALS, 42 healthy participants, and 33 patients with other neurologic diseases.

"It's crucial for patients and their families to be able to discern between ALS and other conditions for diagnostic clarity, prognostic understanding and eligibility to enroll into the appropriate clinical trials," Pantelyat said.

Overall, a set of 33 proteins were identified as a "distinct molecular signature" for ALS that differentiated ALS cases from healthy participants and from other neurologic diseases such as corticobasal syndrome, dementia, Lewy body dementia, multiple system atrophy, Parkinson's disease, and progressive supranuclear palsy.

This model, when combined with other clinical information about the patient, was highly accurate in distinguishing people with ALS from healthy participants and those with other neurologic diseases, with an area under the curve of 98.3%.

The machine learning model was also validated across a group of 13 patients with ALS and 23,601 healthy participants in a control group from the UK Biobank, identifying 82.7% of patients with ALS and 99.3% of participants in the control group.

Among 110 patients and healthy participants in whom plasma samples were taken before ALS symptoms developed, the risk score for ALS generated by the model increased as the time to symptom onset came closer. The ALS risk score was not associated with aging because the association was not seen among healthy participants or in patients with other neurologic diseases.

Potential for Early Diagnosis

Because the protein panel can detect ALS at the earliest stage of disease, it may one day serve as a biomarker for ALS similar to biomarkers seen in the early detection of Alzheimer's disease before symptoms appear.

"We see the light at the end of the tunnel here, and that target is an approved and available blood test for ALS," Pantelyat said. "With a test that allows for earlier detection of ALS, we have opportunities to enroll people in observational studies, and by extension, offer promising disease-modifying — and hopefully disease-stopping — medications, before ALS becomes debilitating."

Some of the proteins in the panel, such as the neurofilament light (NEFL) protein, were already known to be associated with ALS, while 16 additional proteins were identified through predictive modeling as being associated with the disease. The researchers made their data available publicly "to encourage and advance biomarker research" for ALS.

"Fifteen years of cross-institutional collaboration went into this work," Pantelyat said. "Large-scale partnerships are the lifeblood of research. They're what will lead to effective diagnostics and ultimately effective treatments for devastating diseases like ALS."

This study was supported by the Intramural Research Program of the National Institutes of Health, the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, Merck Sharp & Dohme Corporation, and the Italian Ministry of Health. Pantelyat reported no relevant financial relationships. 

https://www.medscape.com/viewarticle/blood-test-detects-als-years-before-symptom-onset-2025a1000ngm