After negative CT for brain injury, a biomarker gap

TBI biomarkers for short-term injury focus on proteins, and autoantibody production is the focus of long-term injury, said Dr. Wu, co-core lab director at Zuckerberg San Francisco General Hospital and professor of laboratory medicine, UCSF School of Medicine.

Autoantibodies are released at the same time as other TBI biomarkers, he said. “We have these biomarkers that are normally sequestered in the central nervous system, that don’t circulate in the blood. And when they show up in blood because we have a disruption of the blood-brain barrier, the theory is that our body recognizes it as foreign and it tends to try to protect itself by raising antibodies.”

Some antibodies are protective and others are not. Those that are not should be the focus, he said, “because pathology results from these autoantibody responses,” not unlike what is seen in type one diabetes, rheumatoid arthritis, or other autoimmune-mediated diseases.

TBI risk stratification is an unmet need, Dr. Wu said. Even among the people who have mild symptoms, “there’s still a need to look for prognosis. And predicting short- and long-term consequences, even with people who have had imaging studies, is the key to moving forward.”

As of now, he said, “neurologists have no tools” to advise whether it is safe to return to sports or work, or to determine whether the patient will have long-term difficulties. “So a lot of gaps in diagnosis and risk stratification and prediction and pathophysiology” of TBIs. “And most importantly, the therapeutics are lagging,” he said. “But because we are biomarker people, it is my hypothesis that you first have to have tools, and then you can start evaluating next-generation pharmacology.”

The pathophysiology of TBIs is complex, Dr. Wu said. “First there’s the acute injury, and the mechanical damage is what we see in the breakdown of the blood barrier and circulating biomarkers.” He calls it the tip of the iceberg. The chronic phase is the bottom of the iceberg, he said, and “we need to know, Is there anything below that iceberg? This is where we have to look at the immune response.”

The central nervous system has what is termed “immune privilege,” he said, drawing from a chapter in a book he and Dr. Peacock co-edited (Kobeissy FH, et al. Autoantibodies in central nervous system trauma: new frontiers for diagnosis and prognosis biomarkers. In: Wu AHB, Peacock WF, eds. Biomarkers for Traumatic Brain Injury. Elsevier Science; 2020:431–445). It means “we have a separate layer of cells, of membranes, that protect us from ourselves. Circulating antibodies don’t enter the central nervous system because the CNS is privileged. And rightfully so,” he said. “We want to protect brain function, and nature and evolution have allowed us to have extra layers of protection.” He describes injury as immune privilege being revoked, “because now you see the breakdown of the blood-brain barrier and the release of macrophages and inflammatory agents that release harmful cytokines and stimulate antibody protection.”

Much research is underway to understand long COVID-19, and the question, Dr. Wu said, is what can be taken from it for understanding TBI. Interleukin-6, which is important in diagnosing concussions (Edwards KA, et al. BMC Neurol. 2020;20[1]:209), is a “harbinger of the kind of cytokine release storm and damage to the neuronal system.”

He and UCSF colleagues have studied IL-6 after COVID. “At least in the reasonable short term, levels do correlate with the disease severity and recovery. But when you have sequelae that come about six months or nine months later, can we use this model to also predict for people who have this TBI sentinel event? I don’t know the answer to that question, but it’s something to consider,” Dr. Wu said (Fitch BA, Lynch KL. Clinical utility of an automated IL-6 immunoassay for COVID19 prognosis and follow-up. Abstract presented at: 2021 AACC Annual Meeting; Sept. 26-30, 2021; Atlanta. Session B-120).

Controlled animal and human studies have demonstrated the detrimental effect of autoantibodies to neuroproteins. One study in which mice were subjected to controlled spinal cord injury demonstrated that autoantibodies potentiate neuronal injury, Dr. Wu said. Wild-type mice were compared with C3-/- knockout mice that don’t have functioning B cells. The data indicated that B cells, through the production of antibodies, affect pathology in such injuries. “If you can’t produce an autoimmune response, does that protect you against injury? This morphologic study seems to suggest the answer is yes,” Dr. Wu said (Ankeny DP, et al. J Clin Invest. 2009;119[10]:2990–2999).

Hypopituitarism is common after TBI and persists for long periods, he said. In a prospective follow-up study of anterior pituitary function in patients with mild, moderate, and severe TBI, Tanriverdi, et al., reported finding elevated pituitary hormone levels up to five years later. Head injury is expected to affect hormonal function, Dr. Wu said. “What I didn’t realize was that it also elicits an autoimmune response” (Tanriverdi F, et al. J Neurotrauma. 2013;30[16]:1426–1433).

In a study of GFAP antibodies, GFAP levels were found to be higher in individuals who have TBI. More interesting, he said, is the higher incidence of GFAP antibodies in those who have poor Glasgow Outcome Scale-Extended scores at six months, relative to those who have higher GOS-E scores and more favorable outcomes. “So there are links to antibody productions” (Zhang Z, et al. PLoS One. 2014;9[3]:e92698).

A study of the consequences of repeated blood-brain barrier disruptions in college football players found changes in S100B autoantibodies. “This was interesting because they had a baseline value—a preseason and postseason value,” Dr. Wu said. Some of the 67 athletes studied had no increase in S100B levels relative to preseason and lower levels of cognitive defects, but a handful had an increase in S100B and neurocognitive changes. “So we have markers that could perhaps predict whether someone is going to have long-term sequelae” (Marchi N, et al. PLoS One. 2013;8[3]:e56805).

“How do we reduce long-term risk?” Dr. Wu asked. One study of mice reported treatment of spinal cord injury with a glycoengineered anti-muCD20 antibody that reduces the development of inflammation and tissue injury by altering the immune system associated with the injury (Casili G, et al. Neurotherapeutics. 2016;13[4]:880–894). Another investigated the role of complement in triggering neuroinflammation after TBI (Alawieh A, et al. J Neurosci. 2018;38[10]:2519–2532).

Intravenous immunoglobulin therapy blocks cytokine release and complement-mediated damage. For patients with TBI, Dr. Wu said, “maybe this should be added to the armamentarium, but you don’t necessarily want to give this to everybody.”

Amy Carpenter Aquino is CAP TODAY senior editor.