NeuroVoices: Charles Bernick, MD, on Blood Biomarkers, Neurodegeneration, and Utility of Observing Professional Fighters

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The neurologist at Cleveland Clinic shared thoughts on a recently published study assessing the relationship between blood biomarkers and change in cognitive function and brain volumes in a cohort of professional fighters.

Charles Bernick, MD

Charles Bernick, MD

Continued exposure to repetitive head impacts (RHI) increases the risk of long-term neurological impairment including chronic traumatic encephalopathy; however, not everyone exposed to RHI will experience neurological decline and among those who do, the onset of symptoms may be years or decades after exposure. Several in the field are looking to identify biomarkers that could be used to detect the development of a neurodegenerative process and/or follow progression over time. Among the biomarkers under investigation, most are either imaging or fluid based.

In October, researchers published data from the Professional Athletes Brain Health Study, a longitudinal cohort study of both active and retired professional fighters. Led by Charles Bernick, MD, 141 active boxers, 211 active Mixed Martial Arts (MMA), 69 retired boxers, and 52 controls had MRI regional volumes extracted, along with plasma levels of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), p-tau231, and N-terminal tau (NTA). Overall, baseline GFAP levels were the highest in the retired boxers (retired boxers vs MMA; P = .0191), whereas active boxers had higher levels of NfL (active boxers vs MMA; P = .047).

Over time, GFAP demonstrated an increase in retired boxers that was associated with decreasing volumes of multiple cortical and subcortical structures (e.g. hippocampus: B = –1.25; 95% CI, –1.65 to –0.85) and increase in lateral ventricle size (B = 1.75; 95% CI, 1.46-2.04). Furthermore, performance on cognitive domains including memory, processing speed, psychomotor speed, and reaction time declined over time with increasing GFAP (e.g., processing speed: B = –0.04; 95% CI, –0.07 to –0.02; reaction time: B = 0.52; 95% CI, 0.28-0.76).

Bernick, a neurologist at Cleveland Clinic, sat down with NeurologyLive® as part of the NeuroVoices series to discuss the data, including how it may change our perception of certain biomarkers in neurodegenerative diseases. In addition, he spoke on the utility of researching patients with RHI, as well as what future research is needed to uncover more about the role of GFAP and other emerging biomarkers.

NeurologyLive®: From a neurologist's standpoint, what are the major takeaways from your study?

Charles Bernick, MD: Well, I don't know if there are any direct clinical takeaways at the moment. What we found is hopefully going to translate into something useful for clinicians in the future. The major findings from the study were that one of the proteins measurable in plasma now, Glial Fibrillary Acidic Protein or GFAP, may be a marker of neurodegeneration in people exposed to repetitive head impacts. In a nutshell, we followed individuals exposed to repetitive head impacts, primarily boxers, and measured GFAP levels over time. We found that those with increasing GFAP levels were more likely, or there was a correlation with declining brain volumes by MRI imaging and declining scores on cognitive testing. The thought is that this marker may reflect ongoing injury in the brain and have a clinical outcome. Now, the problem with the clinical application now is that GFAP is not commercially available yet. And, of course, it has to be validated in other groups, both other cohorts exposed to repetitive head impacts and by other groups as well.

Why did you choose to observe patients with repetitive head impacts specifically?

The work comes from a cohort study, a longitudinal study we call the Professional Athletes Brain Health study. The premise is to understand the long-term consequences of exposure to repetitive head impacts and specifically chronic traumatic encephalopathy (CTE). That was the goal. Initially, 12 years ago, we focused on combat sports, mainly boxers and MMA fighters, due to feasibility and the natural experiment of exposure. The workforce in this study is derived from the longitudinal data from that group, which includes both active and retired athletes.

How does a study like this broaden our understanding of GFAP in neurodegenerative disorders?

GFAP, as you allude to, isn't specific for any disease. It's a marker of Astro gliosis, repaired injury, and inflammation. Presumably, you might see elevations of this in various neurodegenerative conditions, Alzheimer's being one of them. This marker is not disease-specific. Looking at GFAP alone doesn't mean somebody has Alzheimer's disease. Our cohort is much younger, measuring GFAP levels in people in their mid-30s, 40s, 50s, as opposed to the common Alzheimer's group in their mid-70s. The application of something like GFAP may be wider, depending on the groups you're looking at. In a younger population, GFAP elevations probably don't represent Alzheimer's disease, but if you're exposed to repetitive head impacts, it may indicate a different process.

Does this data change our view of biomarkers?

In the future, these plasma biomarkers and where things are going in terms of diagnosis or assessing risk are crucial. We need a better understanding of what these markers represent. Understanding that, for example, ptau 231 may be very specific for Alzheimer's and not affected by other neurodegenerative diseases. Markers like GFAP or neurofilament, another common one we looked at, are very nonspecific. They go up with injury or axonal injury with an NfL, for example. It's about understanding the role of each marker, its specificity, and what it potentially represents.

How do we continue to bring some of these newer markers to the clinic?

I think the way to bring these markers into the clinic is by showing their utility and making it worthwhile for labs to commercialize them. It's already happening in Alzheimer's disease with plasma amyloid markers and plasma ptau 217. With an element like GFAP, there needs to be research validation showing its clinical usefulness to move these things into the clinic.

Are there any types of related research you feel we still need to conduct?

There's a lot to be done in the field of chronic traumatic encephalopathy. It's not a huge public health issue, but for those exposed to repetitive head impacts, there's currently nothing to assess the risk of diseases like CTE. Collaborative work between groups with military cohorts, retired athletes from various sports, is needed to accelerate our knowledge of how these markers perform in different groups. Additionally, we need to look for other biomarkers and explore how combining plasma markers with MRI imaging could increase the accuracy of diagnosis. While the field is moving forward, there's still much to learn, and leveraging work from other disease processes is essential for progress.

REFERENCE
1. Bernick C, Shan G, Ritter A, et al. Blood biomarkers and neurodegeneration in individuals exposed to repetitive head impacts. Alzheimer’s Research & Therapy. 2023;15:173. doi:10.1186/s13195-023-01310-w
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