A Biomarker for Concussion?

Pauline Anderson

December 02, 2015

Researchers have taken another step toward identifying a biomarker for diffuse axonal injury (DAI) in patients with a concussion.

They used immunohistochemistry (IHC) to highlight a cleaved protein called α-II spectrin N-terminal fragment (SNTF), which signals damaged axons in brain tissue, from human donors who had a severe traumatic brain injury (TBI) and from animal models of mild TBI (mTBI).

A test that detects axonal damage could eventually be used to identify the 20% of patients with concussion who experience persistent symptoms, said study author Douglas H. Smith, MD, professor, neurosurgery, and director, Center for Brain Injury and Repair, University of Pennsylvania, Philadelphia.

In patients with a concussion coming to the emergency department, "we want to find out if there was brain damage and if so, what kind of brain damage," Dr Smith told Medscape Medical News.

Knowing that DAI is the pathology at play could help guide research to study "the first ever" potential treatments for concussion, he said.

The new study was published online November 20 in Acta Neuropathologica.

Axons in the brain network are "very selectively vulnerable to damage in a TBI," said Dr Smith. He explained that an injury can cause structural damage to axons in white matter tracts but also chemical damage from enzymes activated by a pathologic concentration of calcium.

Accumulation of the amyloid precursor protein (APP) is the current "gold standard" approach for the diagnosis of DAI, but only a subset of the total population of axons in a given white matter tract accumulates APP after a TBI.

While most people who sustain a concussion recover normal homeostasis in the brain, in patients who have persistent symptoms, the axons may be too damaged. "In some cases, the axons eventually rupture and spill this fragment of a protein that is cleaved by this calcium-activated enzyme out into the brain, and then it gets into the blood," said Dr Smith.

Complementary Study

The new study complements earlier blood biomarker studies. Researchers first identified SNTF in the blood of concussion patients in emergency departments. That marker was found "in the exact same 20% of patients who later on, when we evaluated them 3 months after their injury, had persistent neurocognitive dysfunction," said Dr Smith.

They then looked at blood samples from professional hockey players with a sports-related concussion. "Again, we saw an increase [in SNTF] in the ones with worse symptoms, and it stayed high as these symptoms persisted, and when they felt they could go back to play, it went back down."

The new study investigated SNTF in the brain rather than the blood. Researchers used IHC to compare SNTF in 18 postmortem samples from patients who had experienced a severe TBI and survived for less than 7 days with SNTF in 16 age-matched controls. They also compared a pig model of mTBI at various time points to sham subjects.

Because patients with a concussion almost always survive, it's impossible to get human samples of a brain with a mTBI. To mimic a concussion in pigs, researchers rapidly rotated the head of the animals who were under anesthesia. The animals were sacrificed a few days after the procedure.

In their experiments, researchers compared IHC specific for SNTF to that of APP, as well as to other known markers of axonal pathology. They found SNTF-reactive axons at all time points in both human severe TBI and mTBI. SNTF staining revealed a subpopulation of degenerating axons that were undetected by APP.

Identifying this pathology provides insight into a more comprehensive approach to the neuropathologic assessment of DAI, said Dr Smith. He used the analogy of a suspected myocardial infarction, wherein doctors routinely test for troponins in the blood, which reveals not only that the heart muscle is degenerating but also something about the process.

"This is not like many current methods to simply diagnose concussion in general — this test shows us if there is irreversible damage in the brain and how that damage occurs, specifically providing a diagnosis of diffuse axonal injury," said Dr Smith.

Their data indicate that even a concussion can lead to permanent brain damage, he added. "When those axons degenerate, they can never regrow."

Dr Smith believes that it might actually be more difficult for some concussion patients to recover function than stroke patients because of the "diffuse damage to the network" in the brain.

He sees a blood test that identifies SNTF eventually being used in the emergency department to separate out patients with a concussion who won't soon recover and resume their work, school, or other activities from those who will.

"Discontinuity" of Care

"Now, with concussion there is discontinuity of care; in other words, most patients are only evaluated for a few hours and then sent home," typically with no medical follow-up, he said. He added that it's often up to patients themselves and their families to determine whether there's a problem and, if so, what to do about it.

"There are no evidence-based medicines or therapies — zero," said Dr Smith. Cognitive rest, which used to be generally recommended but has recently been called into question, "has never been proven to be effective."

"We need new diagnostic tools, and so this is the first step in giving us those tools."

If researchers could identify individuals who are destined to have a poor outcome, they could test promising new compounds with this patient group, he said.

"This allows us to make a diagnosis of diffuse axonal injury in some concussed patients, and selectively enroll these individuals in clinical studies so we can finally evaluate patient management strategies, like brain rest, or drug therapies targeting axonal injury."

The researchers are also looking at other axon proteins. "So it could be this one [SNTF] or another one like it, but we believe that this general approach is the way forward."

"Holy Grail"

Asked for his opinion on this research, Frank Conidi, OD, director, Florida Center for Headache and Sports Neurology, and assistant clinical professor of neurology at the Florida State University College of Medicine, Tallahassee, said such efforts to try to find a "cost-effective, easy-to-administer, objective measure of concussion" immediately after an injury is like the "holy grail" in the concussion field.

But he would like to see something like a saliva test that could be performed on the sidelines or in the workplace, without having to go to the emergency department.

What the authors are trying to do in the "big picture" is "excellent," said Dr Conidi, but he raised several issues.

For example, he questioned the velocity used to induce a "concussion" in the pigs, and why they were sacrificed so soon after the procedure. In human models, axonal damage occurs in a later phase of the concussion — sometimes 10 to 14 days later, he said.

Dr Smith explained that the concussion animal model "is well-vetted" through many publications. "The higher rotational acceleration is to account for the smaller brain size to create the same brain tissue deformation as in human TBI," he said.

Another issue is the definition of mTBI, a label often used synonymously with concussion, said Dr Conidi. "I believe that any time you can find an objective measure of brain damage, it's no longer a mild traumatic brain injury; it's a traumatic brain injury," he said. "I don't know about mTBI; I don't even know how to define it."

Dr Smith agreed. "While concussion is alternatively called 'mild TBI', there is nothing mild about it for some individuals," he said. "Indeed, for them, 'mild TBI' is an oxymoron. Potentially, new tools such as blood biomarkers will help distinguish patients who will fully recover from those who won't in the near term. This may lead to new diagnostic terms to describe these differences in injury severity."

This work was supported by grants from the National Institutes of Health, the US Department of Defense, and the National Health Service Research Scotland Career Research Fellowship. Dr Smith has disclosed no relevant financial relationships.

Acta Neuropathol. Published online November 20, 2015. Abstract

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