A study of 81 Australian football players with sports-related concussion suggests that serial biomarker measurements could help identify cases with heightened and prolonged increases in serum glial fibrillary acidic protein and neurofilament light levels, guiding return-to-play decisions based on patients' recovery. Researchers say that the next important step is demonstrating how and when the two proteins should be measured as return-to-play biomarkers.
How long does it take adult athletes' brains to fully recover after a concussion? Can blood biomarkers better estimate return-to-play readiness? A new study published online June 7 in JAMA Network Open provides some insight on these questions and others, as it found that biomarkers of neurobiological recovery could be detected after a sports-related concussion (SRC) and that they persisted over time in subsets of individuals—inviting important consideration for many sports neurologists and their patients.
Looking at 81 Australian football players who had experienced SRC, as well as 56 controls who had not, the study aimed to evaluate levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) at eight time points after injury—24 hours and one, two, four, six, eight, 12, and 26 weeks—as well as to measure cognitive performance, symptoms, and return-to-training times.
“In this cohort study, a subset of SRC cases, particularly those with loss of consciousness, showed heightened and prolonged increases in GFAP and NfL levels that persisted for at least four weeks,” wrote lead author Stuart McDonald, PhD, a senior research fellow in the department of neuroscience at the faculty of medicine at Monash University in Melbourne, Australia, and his colleagues. “These findings suggest that serial biomarker measurement could identify such cases, guiding return-to-play decisions based on neurobiologic recovery.”
Key Findings
The average age of participants was about 23 years for those with concussion and 25 for those without. A majority of both groups were male and White.
The SRC group exhibited higher GFAP levels at 24 hours and four weeks, and higher levels of NfL from one to 12 weeks, compared with the controls. Importantly, participants with SRC who also had loss of consciousness (comprising one-third of all SRC cases) showed higher GFAP at 24 hours, one week, two weeks, and four weeks, as well as higher NfL from one week to 12 weeks compared with SRC participants without loss of consciousness.
The investigators also found that participants in the subgroup with extreme and prolonged increases in GFAP and those with extreme/moderate NfL increases took longer to return to training than those in the moderate GFAP and minimal or no change NfL subgroups. Participants who took longer to return to training also showed higher rates of loss of consciousness; and after stratification by this factor, those with loss of consciousness exhibited larger and more persistent differences in GFAP and NfL.
“The unique thing about this study is not the measure but how many times and how consistently we did it—eight times over six months for 137 athletes,” Dr. McDonald said in a news release accompanying the study. “We demonstrated that blood levels of GFAP are elevated in the vast majority of athletes with concussion at 24 hours, and we are working to have this much-needed diagnostic test approved for use in the next few years.”
However, the authors acknowledged several key limitations—including the disproportionate percentage of men in the analysis as well as the younger ages of participants, meaning these data cannot provide insights into biological sex and age. The sample size was also relatively small, they wrote.
In the future, “our vision is for serial measures of these proteins to be integrated into clinical care, guiding return-to-play decisions based on both symptom and neurobiological recovery,” said Dr. McDonald. “The next important step is demonstrating how and when we should measure these two proteins as return-to-play biomarkers. Our findings take us closer to this becoming a reality.”
Expert Commentary
The current study design was both straightforward and thorough, said Joshua Kamins, MD, associate clinical professor of neurology and associate director of the Steve Tisch BrainSPORT Program at David Geffen School of Medicine at UCLA. Notably, “the authors were able to analyze very acute levels (within 24 hours) and also to track these values out to distant time points, weeks from the initial injury,” and these measures were able to both identify concussive injuries as well as predict subjects with delayed recovery.
Just a few years ago, Dr. Kamins said he would not have believed blood-based biomarkers had a function beyond determining if an injury is more severe than a concussion. Now, “we are seeing that these biomarkers may serve an important function in the near future, by diagnosing and prognosing mild traumatic brain injury/concussion.”
Biomarkers for concussion could achieve two potential goals, he explained: improving the diagnosis of concussion and improving prognosis of concussion, which has a “relatively heterogeneous rate of recovery.”
This first goal can be difficult, he said, “because although imperfect, our history and examination tools—if used in combination—can achieve a sensitivity of greater than 80 percent (JE Resch, et al, 2016). Moreover, taking a history and exam is both quick and free.”
However, for the second goal, “although most adults are symptom-free in fewer than 14 days, 20 to 30 percent of patients have symptoms beyond one month, often lasting months to years. If easy-to-perform tests are able to predict prolonged recovery at day one, or at various time points during the acute window, we would know to whom to direct more aggressive treatment and how to guide our patients.”
The present study adds to a growing body of biomarker literature that should offer hope that we are moving toward the reality of “reliable and useful blood-based biomarkers,” he said.
Still, these tests must be considered experimental at this time. “In particular, caution should be used when interpreting elevated biomarkers outside of the acute window,” Dr. Kamins said. The study's main limitations were well addressed by the authors—”most significantly, the smaller sample size limited the amount of statistical inference that could be made.”
“The challenge with mild traumatic brain injury is that it currently has no established biomarker. If this study is reproducible and well validated, there is the potential for it to offer us a blood biomarker that could help with return-to-play decisions,” said Teena Shetty, MD, MPhil, FAAN, a neurologist and the founder and director of the concussion program in neurology at the Hospital for Special Surgery in New York City.
One main point of interest from this paper, she said, is that some patients who pass currently established post-concussion assessments of full recovery may still be neurobiologically vulnerable even if clinicians are not able to detect this on provocative vestibular, balance, or exertion testing. “This paper suggests that neurobiologic effects may persist even after we clear individuals who are asymptomatic and otherwise pass tests of physical therapy and exertion,” Dr. Shetty said.
The interpretation of loss of consciousness for neurologists who treat concussion already has had a historic evolution, she continued. “Twenty years ago, neurologists believed that loss of consciousness represented a more severe concussion, but that theory has since been reconsidered, with loss of consciousness considered less of a prognostic indicator than initially thought.”
If validated, these findings “may see some providers return to the more conservative return-to-play guidelines that we have moved away from,” Dr. Shetty said. While this paper doesn't disagree with previous research, it may suggest a role for tracking these biomarkers along with the loss of consciousness.
“As someone who sees concussion patients, this paper leads me to want to strengthen the basis for my own return-to-play decisions and also to consider this phenomenon of neurobiologic recovery and how we can better understand and stratify this,” Dr. Shetty said. “At what point can we measure GFAP and NfL? What levels should we concerned about? How do we correlate this to recovery?”
It also points to the fact that we need to better define what neurobiologic recovery means for these patients and if this correlates with patients having a longer recovery time, she said.
This idea of neurobiologic recovery is germane “in part because we know these individuals are more susceptible to a second injury,” Dr. Shetty said. “If that's the concern, how do we determine that the brain has returned to normal using these biomarkers? How do we know that this is enough of a measure and these individuals won't still be at elevated risk?”
Mild traumatic brain injury is challenging because it is a functional injury rather than a structural one, so it can be difficult to validate biomarkers, she explained, adding that returning to exercise continues to offer clear advantages, notwithstanding their potential risks. Given this study, “it's really important to look at increased return-to-play time and cognitive performance and that trajectory and to understand this better,” she added.
Future studies of these biomarkers also would need to look a broader range of ages, different types of athletes, and more women, Dr. Shetty said.
“These biomarkers could theoretically challenge current decisions and influence clinical management if they are validated, but further study must be pursued,” Dr. Shetty told Neurology Today. Generally, she said, “looking at a combination of neurophysiologic imaging and blood markers would be more valuable and more accurate.”
It is not yet clear how to interpret persistently elevated biomarker levels, and these findings should not alter decision-making at this time, Dr. Kamins said. “However, I look forward to a future when we can utilize blood tests to aid in the objective diagnosis of brain injury and provide reliable information to our patients about the expected duration of their recovery.”
https://journals.lww.com/neurotodayonline/fulltext/2024/07180/elevated_blood_biomarkers_may_predict_recovery.3.aspx
O’Brien WT, Spitz G, Xie B, et al. Biomarkers of Neurobiologic Recovery in Adults With Sport-Related Concussion. JAMA Netw Open. 2024;7(6):e2415983. doi:10.1001/jamanetworkopen.2024.15983
Key Points
Question Do distinct trajectory subgroups exist in the serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) following sport-related concussion?
Findings In this cohort study of 81 individuals with sport-related concussion, in a subset of cases, increases in GFAP and NfL levels were substantial and persisted for at least 4 weeks. Individuals in these extreme biomarker subgroups were more likely to have experienced loss of consciousness (LOC) and longer to return to training times.
Meaning The findings of this study suggest the utility of serial measurements of GFAP and NfL to track neurobiologic recovery, with the association between LOC and extended biomarker elevations supporting the use of LOC for informing more conservative return-to-play timelines.
Abstract
Importance Sport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic recovery after SRC.
Objective To examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC.
Design, Setting, and Participants A cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024.
Exposure Sport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms.
Main Outcomes and Measures Primary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times.
Results Eighty-one individuals with SRC (median age, 22.8 [IQR, 21.3-26.0] years; 89% male) and 56 control individuals (median age, 24.6 [IQR, 22.4-27.3] years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference [MD] in natural log, pg/mL, 0.66 [95% CI, 0.50-0.82]) and 4 weeks (MD, 0.17 [95% CI, 0.02-0.32]), and NfL from 1 to 12 weeks (1-week MD, 0.31 [95% CI, 0.12-0.51]; 2-week MD, 0.38 [95% CI, 0.19-0.58]; 4-week MD, 0.31 [95% CI, 0.12-0.51]; 6-week MD, 0.27 [95% CI, 0.07-0.47]; 8-week MD, 0.36 [95% CI, 0.15-0.56]; and 12-week MD, 0.25 [95% CI, 0.04-0.46]). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 [95% CI, 0.77-1.24]), 1 week (MD, 0.27 [95% CI, 0.06-0.49]), 2 weeks (MD, 0.21 [95% CI, 0.004-0.42]) and 4 weeks (MD, 0.34 [95% CI, 0.13-0.55]), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 [95% CI, 0.42-1.03]; 2-week MD, 0.91 [95% CI, 0.61-1.21]; 4-week MD, 0.90 [95% CI, 0.59-1.20]; 6-week MD, 0.81 [95% CI, 0.50-1.13]; 8-week MD, 0.73 [95% CI, 0.42-1.04]; and 12-week MD, 0.54 [95% CI, 0.22-0.85]) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio [IRR], 1.99 [95% CI, 1.69-2.34]; NfL extreme (IRR, 3.24 [95% CI, 2.63-3.97]) and moderate (IRR, 1.43 [95% CI, 1.18-1.72]) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 [95% CI, 1.41-1.93]).
Conclusions and Relevance In this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.
No comments:
Post a Comment