NEW YORK – A team led by researchers at the National Institutes of Health has found that levels of the protein marker neurofilament light (NfL) are correlated with diagnosis and severity of traumatic brain injury (TBI).
In a study published last week in Neurology, the researchers found that serum NfL levels were elevated in TBI patients compared to controls and were elevated in TBI patients whose symptoms lasted longer than one year post-injury compared to patients whose symptoms resolved prior to a year.
They also found that even in patients with mild TBI, NfL remained elevated after several years compared to controls, suggesting that damage from even minor brain injuries may continue to manifest years after the incident, said Pashtun Shahim, a researcher at the NIH Clinical Center and first author on the study.
"The interesting, and probably concerning thing, was that even at five years [following injury] neurofilament light levels were higher than in uninjured or health controls," he said. "That means that even after a single mild traumatic brain injury, we may see signs, long term, of neurodegeneration."
This came as a surprise, Shahim said.
"Prior to this, our understanding was that if you had a mild traumatic brain injury it would just resolve within weeks and then in very, very few cases we would see a more prolonged recovery," he said. "I did not expect that we would see signs on axonal injury at five years. That's a pretty novel thing."
NfL has drawn substantial interest of late as a biomarker linked to a wide range of neurological conditions and neurodegenerative diseases. The marker's profile has been heightened in part through the efforts of high-sensitivity immunoassay firm Quanterix, which owns the most widely used antibodies for measuring the protein and whose technology is capable of detecting it with the sensitivity required to measure it in serum as opposed to the less accessible cerebrospinal fluid.
In 2019, Quanterix acquired Umeå, Sweden-based Uman Diagnostics, the primary supplier of NfL antibodies and ELISA kits, for $22.5 million. The company has since said sales of NfL account for around 20 percent of its revenues. The NIH study used Quanterix's instrumentation and antibody for the Neurology work, Shahim said.
Much of Quanterix's sales of NfL assays have focused on using the protein as a potential tool for monitoring multiple sclerosis patients. The marker has also shown some promise as an aid for diagnosing Alzheimer's disease.
Shahim said the interest in NfL as a potential marker for TBI goes back more than a decade to work done by University of Gotherberg researchers including his coauthors on the Neurology paper, Henrik Zetterberg and Kaj Blennow, measuring levels of the protein in the cerebrospinal fluid of boxers.
"What they saw was that neurofilament light increased after a bout and was related to the number of punches the boxers took to the head," he said. "That was the start of the whole thing."
While the boxing work looked at acute concussion, the NIH study was designed to look at serum NfL levels over a longer period of time. It also compared them to other markers of brain injury, including CSF NfL, functional testing and imaging.
The study looked at two cohorts. The first was composed of 45 hockey players' samples six days after an acute concussion; 31 hockey players with repeat concussions and persistent post-concussion symptoms; 28 control samples from hockey players taken prior to the start of the season; and 14 non-player controls. The second comprised 230 patients enrolled at the NIH Clinical Center, 162 with TBI and 68 controls.
The hockey cohort findings indicated that serum NfL levels were useful for predicting both how long it would take for players to return to play and how long players' post-concussive symptoms would last. NfL levels were 1.3 times higher in players who took longer than 10 days to return to play compared to those who returned in 10 or fewer days. NfL levels were twice as high in players whose post-concussive symptoms lasted longer than a year. Levels also correlated with the number of concussions and the severity of symptoms.
Among the subjects enrolled at NIH, NfL levels were twice as high in TBI patients than controls and highest in patients with severe TBI and lowest in patients with mild TBI. NfL levels also correlated with brain volume and white matter integrity measurements.
Shahim said he and his colleagues at NIH now hope to look at the marker in larger and more diverse cohorts looking, in particular, at patients from different age groups and different injury subtypes.
"The reason we want to do this sort of study is to be able to determine reference ranges for different types of traumatic brain injury," he said. "That would be a very interesting and useful thing to do."
He said the study suggested the marker could prove useful for detecting and managing patients with mild TBI, which is more common and more challenging to diagnose than moderate or severe TBI.
"For moderate and severe traumatic brain injury, we don't need any biomarkers to diagnose it," he said. "We can simply use a CT, for example, and see it."
Mild TBI, on the other hand, can take more time to diagnose.
"We have to use a longer clinical evaluation," Shahim said, noting that NfL could be used to test people suspected of having had mild concussions and then follow them over time.
"In those patients I would use it similarly to cardiac biomarkers like troponin, where you would do multiple assessments on the same patients and see how the blood [NfL] levels change over time," he said.