Brain scans may predict ALS risk in C9ORF72 mutation carriers
188 people related to ALS patient studied to ID markers of disease risk
People with mutations in the C9ORF72 gene who develop amyotrophic lateral sclerosis (ALS) show signs of damage to certain brain regions years before the appearance of disease symptoms, a study reports.
The findings suggest that looking for changes in brain structures could help predict which people with C9ORF72 mutations will develop ALS.
The study, “Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia,” was published in the Annals of Neurology.
The causes of ALS aren’t fully understood, but some cases are associated with genetic mutations. The most common ALS-associated mutation occurs in the C9ORF72 gene. Not everyone who carries a mutation in this gene will develop the disease, however. In fact, estimates suggest less than half the people with the mutation will ever have symptoms of ALS. There’s no reliable way to predict which people with this mutation will develop the disease.
Markers of ALS disease risk
A team led by scientists in the Netherlands enrolled 188 people who were biologically related to someone with ALS caused by a C9ORF72 mutation in a study to identify markers that predicted disease risk in mutation carriers. Fifty-six people were carriers of a C9ORF72 gene mutation and those who didn’t have this mutation were used as a comparison group.
At the study’s start, none of the participants had any symptoms of ALS. The researchers routinely conducted MRI scans to look at structures in the participants’ brains and followed them for several years.
“In this prospective study, we used longitudinal high-resolution T1-weighted MRI scans in a large cohort of asymptomatic [C9ORF72]Â mutation carriers to examine the [brain] structures of those individuals who converted to ALS,” the researchers wrote.
During the follow-up, five C9ORF72 mutation carriers were diagnosed with ALS after a median of nearly six years. One of these patients initially developed a related cognitive disorder called frontotemporal dementia (FTD) and began having ALS symptoms a few years later.
The researchers found through brain scans that those who developed ALS showed signs of atrophy (shrinkage) in certain regions throughout the brain. Atrophy was detectable in the earliest scans taken of these participants up to six years before disease symptoms appeared.
Mathematical models also showed that a sizable fraction of patients who carried a C9ORF72 mutation but had no symptoms by the end of follow-up showed signs of brain atrophy similar to what was seen in those who developed ALS. These participants might be on the way to developing ALS and if they do that means more than 1 in 4 of the mutation carriers would develop disease symptoms by age 80, the researchers said.
More follow-up and validation studies will be needed to confirm this idea, but if it holds true it may be possible to predict if C9ORF72 mutation carriers will develop disease based on brain scans. This could be especially important for research that seeks to prevent the onset of disease in people with this mutation.
“Our results propose a potential new method to quantify presymptomatic disease progression and forecast the timing of clinically manifest [ALS symptoms],” the scientists wrote.
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