Longitudinal Study Links Biomarker Level With Repetitive Head Injury-Associated Neurodegeneration

Elevation of glial fibrillary acidic protein (GFAP) over time is correlated with volumetric losses in the brain and cognitive changes in individuals exposed to repetitive head impacts (RHI). So reveals a study assessing several blood biomarkers against brain imaging and cognitive findings among participants in Cleveland Clinic’s Professional Athletes Brain Health Study over an eight-year period. The findings were published in Alzheimer’s Research & Therapy (2023;15:173).

“As a longitudinal measure, plasma GFAP may have a role in identifying individuals at increased risk of progressive regional atrophy and cognitive decline, which suggests it ultimately might serve as an outcome measure in clinical trials,” says lead investigator Charles Bernick, MD, MPH, a staff neurologist with Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. “Measurements of neurofilament light chain, in contrast, appear to be more useful for reflecting neural injury in individuals actively exposed to repetitive head impacts.”

Backdrop to the study

Begun in 2011, the Professional Athletes Brain Health Study is an ongoing longitudinal study of licensed mixed martial arts (MMA) fighters and boxers exposed to RHI. Participants undergo annual MRI and cognitive testing, as well as blood testing for GFAP, neurofilament light chain (NfL) and tau levels.

Data from the cohort have previously been used to assess the effects of RHI on brain structure over time, to inform criteria for traumatic encephalopathy syndrome and to assess the brain’s potential for repair after exposure to RHI.

Exploration of blood biomarkers and cognitive change

In this analysis, four plasma biomarkers were examined:

• GFAP, a marker of astrocytic injury and degeneration
• NfL, a marker for neuronal injury and degeneration
• p-tau231, a marker of tau phosphorylation
• N-terminal tau, a novel plasma biomarker specific for Alzheimer’s disease (AD) pathology

In studies of traumatic brain injury, all four biomarkers have shown promise, but most of the reports have been limited by short follow-up periods, inclusion of participants exposed to only a single injury or use of limited outcome measures.

The primary aims of the current study were to assess the following:

• Whether baseline biomarker levels were correlated with cognitive performance or MRI regional volume in participants exposed to RHI
• Whether baseline biomarker levels were predictive of subsequent change over time in cognition or MRI regional volume
• Any correlation between the longitudinal trajectory of the biomarkers and change in outcomes over time

The study involved 471 participants across four cohorts:

• 140 active boxers (mean age, 31)
• 211 active MMA fighters (mean age, 30)
• 69 retired boxers (mean age, 49)
• 52 controls with no prior exposure to head impact (mean age, 36)

Data for the study were collected between 2011 and 2018. Baseline assessments included 3T MRI of the brain, plasma sampling and computerized cognitive testing (verbal memory, symbol digit coding, Stroop task and a finger-tapping test). Statistical analyses were performed to assess the relationship between plasma levels and regional brain volumes and cognitive performance at baseline and longitudinally.

Key findings related to the biomarkers studied were as follows:

• GFAP was the only analyte showing an increase over time. Baseline GFAP levels were significantly higher in retired and active boxers compared with the other groups.
• Baseline GFAP was highest among retired boxers, and higher baseline GFAP levels were associated with higher rates of cognitive and MRI volume decline among retired boxers.
• Among retired boxers, increasing GFAP levels over time were associated with decreasing volumes of multiple brain structures and decreased performance on a variety of cognitive domains.
• Levels of NfL were highest in active boxers, in whom NfL levels were inversely associated with baseline brain volumes.
• N-terminal tau and p-tau231 showed no clear relationships to the outcome measures assessed.

Interpreting the findings

The authors note that the increasing levels of GFAP in the retired boxers may reflect underlying neuroinflammation and/or astrogliosis as manifested by loss of regional volume and lower performance on cognitive measures. They also hypothesize that the increased NfL levels in the active boxers may reflect axonal injury from the many blows to the head the athletes typically sustain in training and competition.

“Monitoring plasma GFAP levels over time may help us identify people with prior repeated head impacts who are developing a neurodegenerative process,” Dr. Bernick says. “But without pathological confirmation, there is no way to truly know what type of pathophysiology the plasma GFAP represents.”

He cites this lack of pathological confirmation as the study’s primary limitation, with its strengths being its longitudinal comparison of biomarkers with imaging and cognitive measures in a large population with RHI exposure.

The authors conclude that additional longitudinal studies over longer periods and with additional RHI-exposed cohorts are needed to verify and refine their findings.

Image at top: An astrocyte cell grown in tissue culture stained with antibodies to GFAP and vimentin.

Image credit: GerryShaw, CC BY-SA 3.0, via Wikimedia Commons.