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Friday, February 23, 2024

This Protein Predicts a Brain’s Future After Traumatic Injury

Neil Graham sees a lot of head injuries: “Car accidents, violence, assault, gunshots, stabbing—the works, really,” says Graham, a neurologist from Imperial College London who practices at St. Mary's Hospital nearby.

Doctors stop the bleeding, they relieve any pressure building inside the skull, maybe they’ll put the patient into a coma to keep the brain from overworking when it needs to relax and heal. Imaging can also help—to an extent. CT scans or MRIs pinpoint bruising or specks of hemorrhage in gray matter, the brain's outer layer where neurons do most of their processing. But a clean scan isn’t a clean bill of health. Trauma to axons—a neuron's root-like fibers that extend toward other neurons—often appears only in the deeper white matter, sometimes eluding simple scans.

Axonal damage is a big deal. Cognition and motor function tank when neurons can’t exchange messages. And when white matter absorbs a blow, the fallout not only can linger, it can worsen, causing severe problems for thinking or movement. But doctors don't always know about that damage. It’s then hard to give survivors assurances about the future. “The families and the patients are asking us early on, ‘Well what’s it going to look like in six months or a year? When can I get back to work?’” says David Sharp, a professor of neurology at Imperial College London who also practices at St. Mary’s.

Sharp and Graham think they can find the answer in proteins, or biomarkers, carried in a person’s blood. They teamed up with trauma experts across Europe for a study that followed nearly 200 patients with head injuries for one year. The researchers pored over brain scans, plasma analyses, and white matter fluid samples, tracking how five biomarkers correlate with an injury’s severity—and the person’s recovery. In results published in September in Science Translational Medicine, they focused on one protein in particular: neurofilament light (NfL). NfL levels rise for weeks after an injury and can stay high a year later.

Plasma NfL won’t tell you where axonal damage is, but it’s an easier way of measuring damage—and tracking it long-term—compared to advanced MRI techniques.

“Brain injury, you think of it as a single event: Someone has an injury and that's it, they recover or they don't,” says Richard Sylvester, a neurologist at London’s National Hospital for Neurology who was not involved in the study. “But we know that there's an ongoing process.”

Biomarkers are valuable indicators, because they help doctors focus on pathology rather than symptoms. Symptoms can be vague, based on the patient’s subjective experience. They tell you what effect some injury has caused, not what the injury actually is. Biomarkers, however, can be like molecular receipts that point to particular processes, such as axons shearing apart.

When a patient presents with an ambiguous symptom like chest pain, for example, cardiologists can test for biomarkers like troponins and use that information to differentiate between a heart attack or something less severe, like gas or a pulled muscle. "You drill down. You get a specific pathological diagnosis," says Graham.

When it comes to head injuries, "we need a way to differentiate the psychological from the neurological," he says. "It's not about syndromes and symptoms, it's more about a hard biomarker or diagnostic evidence of problems as we would in most other areas of medicine."

But brain biomarkers are tricky. Those proteins circulate in the cerebrospinal fluid more than in the blood. Since lumbar punctures that sample that fluid are far more invasive than blood draws, brain biomarkers were long off limits. That’s begun to change. Biosensing instruments have become more sensitive and can now catch the tiny fraction of neural proteins that leak into the blood.

In healthy brains, neurofilament light is a long, thin protein. Its chain of peptides link up with others, end-to-end, like structural nunchucks that span the length of axons. Along with light’s larger cousins, medium and heavy, the neurofilaments provide the skeleton needed for axons to function.

Increased levels of NfL are a sign that something is amiss in the nervous system. High levels of NfL have been linked to dementia and multiple sclerosis. In multiple sclerosis, where damaged axons cause nervous system communication to break down, the NfL level in spinal fluid is sometimes the only clinical gauge of how active the disease is—and how severe it may become. Past studies have fueled hopes that Nfl is a good proxy for axonal damage, but neurologists haven’t had the long-term patient data necessary to deduce the extent of damage from head trauma based on Nfl levels. In fact, researchers weren’t even sure whether the level of the biomarker in the blood even correlates with levels in the brain.

Graham and Sharp were also curious about four other biomarkers found in the blood. There was Tau, another neuronal skeleton protein linked to Alzheimer’s; UCH-L1, an enzyme; and S100B and GFAP, two proteins found in the brain’s glial cells, not neurons. They wanted to tease out the “kinetics” for these biomarkers. Do the levels spike immediately after an injury, then promptly drop? Or do they plateau—a sign of prolonged degeneration?

But before they could find any patterns, they needed a diverse group of patients, so they could root out confounding factors like age. They teamed up with doctors at eight trauma centers in England, Italy, Slovenia, and Switzerland; 197 of their patients with recent head injuries agreed to participate for a year. People got brain scans and blood tests within 10 days of their injuries. Over the following 12 months, each doctor continued measuring biomarkers in each person’s plasma and assessing their symptoms.

Using conventional blood draws, the team tracked changes in the levels of each biomarker. They found that Tau, UCH-L1, S100B, and GFAP peaked within 24 hours after injuries. But NfL behaved differently. Its levels rose for weeks. NfL usually peaked around 20 days after injuries, at concentrations 85 times higher than healthy levels. The biggest increases correlated with more severe outcomes. Six months after the injury, dozens of subjects still had elevated NfL; 12 months later, many were still abnormal.

The team used a standard outcome scale ranging from 1 to 8—from death to complete recovery—and deemed a score of 6 (mild disability) or above to be “favorable.” A person’s peak NfL levels in the first few weeks correlated most closely with whether they recovered favorably six or 12 months later. People with higher levels tended to fare worse. NfL predicted this better than any other biomarker.

Eighteen other participants had small devices implanted into their white matter to collect NfL. Simultaneous blood draws revealed concrete proof that blood NfL reflects the brain’s.

The team confirmed the correlation between NfL levels and injury severity with a nonstandard MRI analysis called diffusion tensor imaging, and brain volume measurements. They also did a follow-up test with lab animals. They gave rats one of two controlled brain injuries: Either mild or more moderate. NfL showed up in the rats’ blood, too, and again, the levels of NfL in their plasma was markedly higher for those with the moderate versus mild injuries.

“We’re now trying to pull this into clinical practice,” says Sharp, “really to change the way that we're managing our patients on the ground.”

During the study period, Graham recalls, one man showe up at St. Mary’s after falling off his bicycle. Though he had worn a helmet, the man blacked out once his head struck the ground, and later he couldn't shake an odd feeling of confusion, known as “post-traumatic amnesia.” His CT and the MRI looked fine. The man was discharged—but Graham’s team was dubious. Suspecting hidden damage, Graham recruited this man to the study. Blood tests revealed details missing from brain imaging: The man's NfL levels were way up, an indicator of significant axonal damage.

In the future, the study authors believe, NfL levels could help doctors make treatment decisions; if a doctor knows that their patient has axonal damage, they can adjust the therapy accordingly. For instance, if a patient has high NfL levels, Graham says, they become “particularly good candidates” for experimental anti-inflammatory treatments to ward off more cell death. Following NfL—not just as a one-off measurement—would also help a doctor gauge how well the treatment works.

“NfL is really very promising,” says Ina Wanner, a neuroscientist with UCLA's Brain Injury Research Center, who is not part of the European team but studies the biomarker. Brain biomarkers have always faced a “detection” challenge. Wanner says that this underscores why showing such a large—and lasting—increase in NfL is so important: It means that the protein isn’t just relevant, it’s also measurable.

“The technology is evolving,” says Pashtun Shahim, a physician with the National Institutes of Health who studies neural biomarkers for rehab medicine. We’re a long way from detecting small amounts of NfL via point-of-care devices like glucose monitors, he says. But he expects an increasing number of hospitals to add neural proteins to routine panels in head injuries.

Sylvester’s hospital has an instrument that’s sensitive enough to measure NfL, and he is eager to use the biomarker more in his practice. “We're still not 100 percent sure how to use it,” he says, though he says this study was eye-opening. “It starts getting interesting when you can actually say what's going on in the brain and correlate that very closely with the clinical experience.”

In Graham’s practice, his experience with the patient with the biking injury reinforced what he suspected about the power of biomarkers. The man began seeing a neuropsychologist, whose job is to help with the anxiety that accompanies post-traumatic amnesia and to provide cognitive rehab to help people regain memory. By the six-month assessment mark, the man had made a full recovery.

When the man’s NfL results later confirmed that he’d suffered axonal damage that didn’t show up on early brain scans, Graham was impressed by NfL’s potential. What pleases him now is thinking that the days of resorting to hunches may be numbered.

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