Blood Protein Biomarker Panel Predicts ALS Symptom Onset Within Two Years
核心洞察
Researchers identified a panel of 19 blood proteins, including neurofilament light chain (搜索) (NfL), that can estimate time to ALS symptom onset with an average error of approximately 18 months.
The study analyzed plasma samples from 137 participants in the NIH-funded Pre-symptomatic Familial ALS (Pre-fALS) study using high-throughput proteomic analysis, identifying 92 differentially expressed proteins.
Predictive models were validated across time horizons from six months to five years and produced similar results using UK Biobank data, suggesting broader population relevance.
Months to several years before amyotrophic lateral sclerosis (搜索) (ALS) symptoms arise, levels of certain blood proteins may dramatically shift — a discovery that could transform how clinicians approach the neurodegenerative disease. Researchers analyzing data from the long-running, National Institutes of Health (NIH)-funded Pre-symptomatic Familial ALS (Pre-fALS) study have identified a panel of 19 blood proteins capable of predicting when a genetically at-risk individual will develop clinically manifest ALS, with an average prediction error of approximately 18 months.
"If someone carrying an ALS-associated genetic variant had asked me in the past when they would become symptomatic, I would have struggled to provide a reasonable estimate," said Michael Benatar, M.D., Ph.D., senior author and professor of neurology and public health sciences at the University of Miami. "These biomarkers give us a far better idea of the timing, allowing us to estimate the time to symptom onset with an average error of about 18 months. That's something we can work with."
Two Decades of Pre-Symptomatic Surveillance
For nearly 20 years, the Pre-fALS study, led by Benatar and Joanne Wuu, Sc.M., research associate professor of neurology and public health sciences at the University of Miami, has collected data and biological samples from people at significantly elevated genetic risk for ALS who have not yet progressed, or phenoconverted, to the disease. While this cohort is unique in permitting the examination of presymptomatic ALS, recent studies suggest that findings from Pre-fALS are likely relevant to the broader population.
A pivotal 2017 analysis of ten Pre-fALS participants who had developed symptoms demonstrated that neurofilament light chain (搜索) (NfL), a structural protein in neurons, spiked in their blood in the months preceding ALS phenoconversion. As more study participants have since begun showing symptoms or signs of disease, new opportunities to search for additional pre-symptomatic ALS biomarkers have emerged.
Proteomic Discovery and Machine Learning Validation
The investigators applied a high-throughput proteomic analysis method called Olink to plasma samples from 137 study participants, 33 of whom had demonstrated clinical manifestations of ALS or frontotemporal dementia (搜索). After measuring levels of more than 5,000 proteins, the team identified 92 whose levels differed in people before they eventually showed symptoms.
Using machine-learning techniques, the authors tested how various combinations of proteins could predict future risk of phenoconversion. They settled on a select panel of 19 proteins, including NfL, that maximized predictive accuracy across time horizons ranging from six months to five years. The researchers demonstrated that, with data on these 19 proteins, their predictive models could estimate a patient's onset within less than two years of the actual time that they showed signs of disease.
The team also produced similar results using data from the UK Biobank, which, despite some limitations, is more representative of the general population than the genetically predisposed cohort of Pre-fALS.
A Path Toward Preventative Intervention
"With preventative gene-targeting treatments now becoming available, there is a particularly urgent need for reliable biofluid-based signatures that indicate near-term onset in individuals that carry ALS risk genes," said Amy Bany Adams, Ph.D., acting director of NIH's National Institute of Neurological Disorders and Stroke (NINDS).
The clinical relevance of these biomarkers is already being tested. Tofersen, a drug approved for symptomatic ALS, is currently being evaluated as a preventative therapeutic in pre-symptomatic ALS through ATLAS, a clinical trial designed by Benatar in partnership with Biogen. ATLAS will test whether starting treatment shortly before symptoms appear could avert or delay the onset of ALS.
"This is all possible because of the members of the carrier community who believe in our mission of preventing ALS and have supported and participated in our research. It has been one of my life's greatest privileges to give something back," Benatar said.
The research was supported by NIH through NINDS grants R01NS105479 and U54NS092091.