Blood protein panel may help forecast ALS symptom onset in gene carriers

A panel of 19 blood proteins may help estimate when symptoms of amyotrophic lateral sclerosis (ALS) will emerge in people who carry disease-associated genetic variants, a new study suggests. When the model was tested using data from carriers whose symptom-onset dates were known, its estimates differed from the actual timing by an average of 1.6 years.

“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,” Michael Benatar, MD, PhD, senior author of the study at the University of Miami, said in a press release. “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.”

The study, “Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS,” was published in Nature Medicine. The work was funded by the National Institutes of Health (NIH), the Muscular Dystrophy Association, the ALS Association, and other organizations.

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Protein panel could help shape ALS prevention trials

Researchers are hopeful that the new protein panel could help identify gene carriers at greatest near-term risk of developing symptoms for enrollment in ALS prevention trials.

“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, PhD, acting director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS), who was not directly involved in the study.

The causes of ALS are not fully understood, but in some cases the disease is caused by or linked to genetic variants. Such variants are especially relevant in familial ALS, in which multiple members of the same family are affected.

These genetic variants are present from birth, but symptoms, if they develop, often do not emerge until adulthood. Researchers have had limited ability to predict whether or when a carrier will develop symptoms.

Here, an international team of scientists set out to identify blood markers that could help predict when symptoms would appear in people carrying ALS-associated genetic variants. They used proteomics, a method that measures large numbers of proteins at once, and then applied statistical analyses to identify meaningful patterns.

This study included 35 people with ALS, 59 people without the disease who did not carry an ALS-associated genetic variant, and 10 people who carried such a variant but had not developed any symptoms. The study also included samples from 33 phenoconverters — mutation carriers who didn’t have symptoms at the start of the study but developed symptoms of ALS and/or frontotemporal dementia over the course of follow-up. Crucially, most of the phenoconverters had blood samples on file from both before and after symptom onset.

By analyzing more than 500 blood samples collected over time, the researchers identified dozens of proteins whose levels changed in the months and years before symptom onset. They then narrowed the list to a panel of 19 blood proteins that helped estimate when symptoms would occur. In the researchers’ models, estimates based on the panel differed from the actual timing by an average of less than two years.

“We were able to estimate years to phenoconversion with an [average error] of 1.6 years,” the researchers wrote, adding that this error rate “represents a considerable advancement with practical implications and provides a temporal anchor for interpretating data from carriers who have not phenoconverted.”

“For example, a prevention trial that aims to enroll individuals with an estimated time to phenoconversion of 2 years (or less), based on this protein panel, would require a follow-up duration of ~3.6 years, which is eminently feasible,” they added.

U.K. data offer partial support for protein panel findings

The researchers partially replicated their findings using data from a separate study in the U.K. In that study, only 15 of the 19 proteins in the panel had been measured. The 15-protein panel estimated time to the approximated onset of symptoms with an average error of 2.75 years. Because exact symptom-onset dates were not available in the U.K. data, however, the researchers viewed the findings as supportive rather than confirmatory.

Although further work is needed to validate the 19-protein panel’s predictive performance, the scientists are hopeful that it may provide a useful tool for clinical trials aimed at preventing or delaying ALS symptom onset.

Theoretically, the panel could be used to identify mutation carriers who are at high risk of developing symptoms in the near future, and those carriers could then be enrolled in prevention trials.

“Clinical trials that aim to prevent phenoconversion to clinically manifest ALS/FTD will need to enrich the study population for those at greatest short-term risk of the primary outcome measure that will be used to quantify treatment effect. As such, our identification of a panel of proteins that reliably predict the occurrence and timing of phenoconversion represents an important advance in furthering the ultimate goal of ALS prevention,” the scientists concluded.