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. 2023 May 1;6(5):e2316601.
doi: 10.1001/jamanetworkopen.2023.16601.

Longitudinal Associations of Clinical and Biochemical Head Injury Biomarkers With Head Impact Exposure in Adolescent Football Players

Taylor R Zuidema  1   2 , Jeffrey J Bazarian  3 , Kyle A Kercher  1 , Rebekah Mannix  4 , Reuben H Kraft  5   6 , Sharlene D Newman  7 , Keisuke Ejima  8 , Devin J Rettke  1 , Jonathan T Macy  9 , Jesse A Steinfeldt  10 , Keisuke Kawata  1   2
Affiliations

Longitudinal Associations of Clinical and Biochemical Head Injury Biomarkers With Head Impact Exposure in Adolescent Football Players

Taylor R Zuidema et al. JAMA Netw Open. .

Abstract

Importance: Consequences of subconcussive head impacts have been recognized, yet most studies to date have included small samples from a single site, used a unimodal approach, and lacked repeated testing.

Objective: To examine time-course changes in clinical (near point of convergence [NPC]) and brain-injury blood biomarkers (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1], and neurofilament light [NF-L]) in adolescent football players and to test whether changes in the outcomes were associated with playing position, impact kinematics, and/or brain tissue strain.

Design, setting, and participants: This multisite, prospective cohort study included male high school football players aged 13 to 18 years at 4 high schools in the Midwest during the 2021 high school football season (preseason [July] and August 2 to November 19).

Exposure: A single football season.

Main outcomes and measures: The main outcomes were NPC (a clinical oculomotor test) and serum levels of GFAP, UCH-L1, and NF-L. Participants' head impact exposure (frequency and peak linear and rotational accelerations) was tracked using instrumented mouthguards, and maximum principal strain was computed to reflect brain tissue strain. Players' neurological function was assessed at 5 time points (preseason, post-training camp, 2 in season, and postseason).

Results: Ninety-nine male players contributed to the time-course analysis (mean [SD] age, 15.8 [1.1] years), but data from 6 players (6.1%) were excluded from the association analysis due to issues related to mouthguards. Thus, 93 players yielded 9498 head impacts in a season (mean [SD], 102 [113] impacts per player). There were time-course elevations in NPC and GFAP, UCH-L1, and NF-L levels. Compared with baseline, the NPC exhibited a significant elevation over time and peaked at postseason (2.21 cm; 95% CI, 1.80-2.63 cm; P < .001). Levels of GFAP and UCH-L1 increased by 25.6 pg/mL (95% CI, 17.6-33.6 pg/mL; P < .001) and 188.5 pg/mL (95% CI, 145.6-231.4 pg/mL; P < .001), respectively, later in the season. Levels of NF-L were elevated after the training camp (0.78 pg/mL; 95% CI, 0.14-1.41 pg/mL; P = .011) and midseason (0.55 pg/mL; 95% CI, 0.13-0.99 pg/mL; P = .006) but normalized by the end of the season. Changes in UCH-L1 levels were associated with maximum principal strain later in the season (0.052 pg/mL; 95% CI, 0.015-0.088 pg/mL; P = .007) and postseason (0.069 pg/mL; 95% CI, 0.031-0.106 pg/mL; P < .001).

Conclusions and relevance: The study data suggest that adolescent football players exhibited impairments in oculomotor function and elevations in blood biomarker levels associated with astrocyte activation and neuronal injury throughout a season. Several years of follow-up are needed to examine the long-term effects of subconcussive head impacts in adolescent football players.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bazarian reported receiving research support and speaker fees from Abbott Diagnostics, participating in a research report for BrainScope, and receiving grants from the National Institutes of Health (NIH) and BRAINBox Solutions Inc outside the submitted work. Dr Kercher reported receiving grants from the NIH during the conduct of the study. Dr Mannix reported receiving grants from Abbott Laboratories and the National Football League outside the submitted work. Dr Kraft reported receiving grants from the National Science Foundation during the conduct of the study and having a financial interest in BrainSim Technologies Inc, a company that could potentially benefit from the results of this research outside the submitted work; this interest has been reviewed by Penn State University in accordance with its Individual Conflict of Interest policy for the purpose of maintaining the objectivity and integrity in research and is being managed by Pennsylvania State University. Prof Kawata reported receiving grants from the NIH and the Indiana State Department of Health during the conduct of the study and outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
NPC indicates near point of convergence.
Figure 2.
Figure 2.. Time-Course Changes in Near Point of Convergence (NPC) Overall and by Player Position
Data were collected during the 2021 preseason (July [T1]), after training camp (August [T2]), during the season (September [T3] and October [T4]), and postseason (November or December [T5]). Whiskers indicate standard error of the mean.
Figure 3.
Figure 3.. Time-Course Changes in Blood Biomarker Levels Overall and by Player Position
Data were collected during the 2021 preseason (July [T1]), after training camp (August [T2]), during the season (September [T3] and October [T4]), and postseason (November or December [T5]). E. P < .001 vs preseason for all comparisons. GFAP indicates glial fibrillary acidic protein; NF-L, neurofilament light; and UCH-L1, ubiquitin C-terminal hydrolase-L1. Whiskers indicate standard error of the mean. aP < .01 vs preseason. bP < .001 vs preseason. cP < .05 vs preseason.
Figure 4.
Figure 4.. Associations Between Changes in Ubiquitin C-Terminal Hydrolase-L1 (UCH-L1) and Tissue Strain and Kinematic Variables
Orange lines are estimated slope based on regression models; shading represents 95% CIs. MPS indicates maximum principal strain; T4, during the season (October 2021); and T5, postseason (November or December 2021).
See this image and copyright information in PMC

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