The purpose of the study was to examine an association of repetitive subconcussive head impacts with changes in plasma neurofilament light (NF-L) levels following 10 bouts of controlled soccer heading. In this randomized control trial, 37 healthy adult soccer players were randomly assigned into either a heading (n = 19) or kicking-control group (n = 18). The heading group executed 10 headers with soccer balls projected at a velocity of 25 mph over 10 min. Plasma samples were obtained at pre-heading baseline, 0 h, 2 h, and 24 h post-heading. The kicking-control group followed the same protocol with 10 kicks. Plasma NF-L was measured using ultrasensitive single-molecule array technology. Data from 34 subjects were eligible for analysis (heading n = 18 and kicking n = 16). Ten subconcussive head impacts induced a gradual increase in plasma NF-L expression for the heading group (β = 0.0297, standard error [SE] = 0.01, p = 0.0049), whereas there was no significant time effect for the kicking-control group. A follow-up analysis revealed that a significant difference appeared at 24 h post-heading (3.68 ± 0.30 pg/mL) compared with pre-heading (3.12 ± 0.29 pg/mL, p = 0.0013; Cohen's d = 1.898). At the 24 h post-heading time-point, the plasma NF-L level for the heading group was significantly higher than that of the kicking-control group with an estimated mean difference of 0.66 pg/mL (SE = 0.22, p = 0.0025). The data suggest that the increased level of plasma NF-L was driven by repetitive subconcussive head impacts and required longer than 2 h after the head impacts for the increase to be detected. Plasma NF-L levels may serve as an objective marker to monitor acute axonal burden from subconcussive head impacts.
Get full access to this article
View all access options for this article.
References
1.
BailesJ.E., PetragliaA.L., OmaluB.I., NaumanE., and TalavageT. (2013). Role of subconcussion in repetitive mild traumatic brain injury. J. Neurosurg., 119, 1235–1245.
2.
BeckwithJ.G., GreenwaldR.M., ChuJ.J., CriscoJ.J., RowsonS., DumaS.M., BroglioS.P., McAllisterT.W., GuskiewiczK.M., MihalikJ.P., AndersonS., SchnebelB., BrolinsonP.G., and CollinsM.W. (2013). Timing of concussion diagnosis is related to head impact exposure prior to injury. Med. Sci. Sports Exerc., 45, 747–754.
3.
LiptonM.L., KimN., ZimmermanM.E., KimM., StewartW.F., BranchC.A., and LiptonR.B. (2013). Soccer heading is associated with white matter microstructural and cognitive abnormalities. Radiology, 268, 850–857.
4.
AloscoM.L., TripodisY., JarnaginJ., BaughC.M., MartinB., ChaissonC.E., EstochenN., SongL., CantuR.C., JerominA., and SternR.A. (2017). Repetitive head impact exposure and later-life plasma total tau in former National Football League players. Alzheimers Dement. (Amst.) 7, 33–40.
5.
AhmadzadehH., SmithD.H., and ShenoyV.B. (2014). Viscoelasticity of tau proteins leads to strain rate-dependent breaking of microtubules during axonal stretch injury: predictions from a mathematical model. Biophys. J., 106, 1123–1133.
6.
YapY.C., KingA.E., GuijtR.M., JiangT., BlizzardC.A., BreadmoreM.C., and DicksonT.C. (2017). Mild and repetitive very mild axonal stretch injury triggers cystoskeletal mislocalization and growth cone collapse. PLoS One, 12, e0176997.
7.
ElderG.A., Gama SosaM.A., De GasperiR., StoneJ.R., DicksteinD.L., HaghighiF., HofP.R., and AhlersS.T. (2015). Vascular and inflammatory factors in the pathophysiology of blast-induced brain injury. Front. Neurol., 6, 48.
8.
HallA.A., MendozaM.I., ZhouH., ShaughnessM., Maudlin-JeronimoE., McCarronR.M., and AhlersS.T. (2017). Repeated low intensity blast exposure is associated with damaged endothelial glycocalyx and downstream behavioral deficits. Front. Behav. Neurosci., 11, 104.
9.
KawataK., RubinL.H., LeeJ.H., SimT., TakahagiM., SzwankiV., BellamyA., DarvishK., AssariS., HendererJ.D., TierneyR., and LangfordD. (2016). Association of football subconcussive head impacts with ocular near point of convergence. JAMA. Ophthalmol., 134, 763–769.
10.
KawataK., TierneyR., PhillipsJ., and JekaJ.J. (2016). Effect of repetitive sub-concussive head impacts on ocular near point of convergence. Int. J. Sports Med., 37, 405–410.
11.
HaranF.J., TierneyR., WrightW.G., KeshnerE., and SilterM. (2013). Acute changes in postural control after soccer heading. Int. J. Sports Med., 34, 350–354.
12.
HwangS., MaL., KawataK., TierneyR., and JekaJ.J. (2017). Vestibular dysfunction after subconcussive head impact. J. Neurotrauma, 34, 8–15.
13.
KawataK., RubinL.H., TakahagiM., LeeJ.H., SimT., SzwankiV., BellamyA., TierneyR., and LangfordD. (2017). Subconcussive impact-dependent increase in plasma s100beta levels in collegiate football players. J. Neurotrauma, 34, 2254–2260.
14.
OliverJ.M., JonesM.T., KirkK.M., GableD.A., RepshasJ.T., JohnsonT.A., AndreassonU., NorgrenN., BlennowK., and ZetterbergH. (2016). Serum neurofilament light in american football athletes over the course of a season. J. Neurotrauma, 33, 1784–1789.
15.
AbbasK., ShenkT.E., PooleV.N., BreedloveE.L., LeverenzL.J., NaumanE.A., TalavageT.M., and RobinsonM.E. (2015). Alteration of default mode network in high school football athletes due to repetitive subconcussive mild traumatic brain injury: a resting-state functional magnetic resonance imaging study. Brain Connect. 5, 91–101.
16.
JohnsonB., NeubergerT., GayM., HallettM., and SlobounovS. (2014). Effects of subconcussive head trauma on the default mode network of the brain. J. Neurotrauma, 31, 1907–1913.
McKeeA.C., SternR.A., NowinskiC.J., SteinT.D., AlvarezV.E., DaneshvarD.H., LeeH.S., WojtowiczS.M., HallG., BaughC.M., RileyD.O., KubilusC.A., CormierK.A., JacobsM.A., MartinB.R., AbrahamC.R., IkezuT., ReichardR.R., WolozinB.L., BudsonA.E., GoldsteinL.E., KowallN.W., and CantuR.C. (2013). The spectrum of disease in chronic traumatic encephalopathy. Brain, 136, 43–64.
19.
MezJ., DaneshvarD.H., KiernanP.T., AbdolmohammadiB., AlvarezV.E., HuberB.R., AloscoM.L., SolomonT.M., NowinskiC.J., McHaleL., CormierK.A., KubilusC.A., MartinB.M., MurphyL., BaughC.M., MontenigroP.H., ChaissonC.E., TripodisY., KowallN.W., WeuveJ., McCleanM.D., CantuR.C., GoldsteinL.E., KatzD.I., SternR.A., SteinT.D. and McKeeA.C. (2017). Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 318, 360–370.
20.
KawataK., LiuC.Y., MerkelS.F., RamirezS.H., TierneyR.T., and LangfordD. (2016). Blood biomarkers for brain injury: what are we measuring?. Neurosci. Biobehav. Rev., 68, 460–473.
21.
ShahimP., GrenM., LimanV., AndreassonU., NorgrenN., TegnerY., MattssonN., AndreasenN., OstM., ZetterbergH., NellgardB., and BlennowK. (2016). Serum neurofilament light protein predicts clinical outcome in traumatic brain injury. Sci. Rep., 6, 36791.
22.
LjungqvistJ., ZetterbergH., MitsisM., BlennowK., and SkoglundT. (2017). Serum neurofilament light protein as a marker for diffuse axonal injury: results from a case series study. J. Neurotrauma, 34, 1124–1127.
23.
ShahimP., ZetterbergH., TegnerY., and BlennowK. (2017). Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology, 88, 1788–1794.
24.
HwangS., MaL., KawataK., TierneyR., and JekaJ.J. (2017). Vestibular dysfunction after subconcussive head impact. J. Neurotrauma., 34, 8–15.
25.
IgarashiK., HottaK., ImaiK., YamaguchiY., ItoS., KawataN., TanakaM., KakushimaN., TakizawaK., MatsubayashiH., EndoM., AsakuraK., OishiT., ShimodaT., and OnoH. (2017). Can positron emission tomography detect colorectal adenomas and cancers?. J. Gastroenterol. Hepatol., 32, 602–608.
26.
KuhleJ., BarroC., AndreassonU., DerfussT., LindbergR., SandeliusA., LimanV., NorgrenN., BlennowK., and ZetterbergH. (2016). Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin. Chem. Lab. Med., 54, 1655–1661.
27.
WilsonD.H., RissinD.M., KanC.W., FournierD.R., PiechT., CampbellT.G., MeyerR.E., FishburnM.W., CabreraC., PatelP.P., FrewE., ChenY., ChangL., FerrellE.P., von EinemV., McGuiganW., ReinhardtM., SayerH., VielsackC., and DuffyD.C. (2016). The Simoa HD-1 Analyzer: a novel fully automated digital immunoassay analyzer with single-molecule sensitivity and multiplexing. J. Lab. Autom., 21, 533–547.
28.
ZetterbergH., JonssonM., RasulzadaA., PopaC., StyrudE., HietalaM.A., RosengrenL., WallinA., and BlennowK. (2007). No neurochemical evidence for brain injury caused by heading in soccer. Br. J. Sports Med., 41, 574–577.
29.
RohrerJ.D., WoollacottI.O., DickK.M., BrotherhoodE., GordonE., FellowsA., ToombsJ., DruyehR., CardosoM.J., OurselinS., NicholasJ.M., NorgrenN., MeadS., AndreassonU., BlennowK., SchottJ.M., FoxN.C., WarrenJ.D., and ZetterbergH. (2016). Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology, 87, 1329–1336.
30.
WestonP.S.J., PooleT., RyanN.S., NairA., LiangY., MacphersonK., DruyehR., MaloneI.B., AhsanR.L., PembertonH., KlimovaJ., MeadS., BlennowK., RossorM.N., SchottJ.M., ZetterbergH., and FoxN.C. (2017). Serum neurofilament light in familial Alzheimer disease: a marker of early neurodegeneration. Neurology, 89, 2167–2175.
31.
BaciogluM., MaiaL.F., PreischeO., SchelleJ., ApelA., KaeserS.A., SchweighauserM., EningerT., LambertM., PilottoA., ShimshekD.R., NeumannU., KahleP.J., StaufenbielM., NeumannM., MaetzlerW., KuhleJ., and JuckerM. (2016). Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron, 91, 494–496.
32.
FIFA. (2007). FIFA Big Count 2006: 270 million people active in football. FIFA Communications Division, Information Services, May 31, 2007. https://www.fifa.com/mm/document/fifafacts/bcoffsurv/bigcount.statspackage_7024.pdf (Last accessed April9, 2018).
33.
DorminyM., HoogeveenA., TierneyR.T., HigginsM., McDevittJ.K., and KretzschmarJ. (2015). Effect of soccer heading ball speed on S100B, sideline concussion assessments and head impact kinematics. Brain Inj. 25, 1–7. [E-pub ahead of print.]
34.
BretzinA.C., MansellJ.L., TierneyR.T., and McDevittJ.K. (2017). Sex differences in anthropometrics and heading kinematics among Division I soccer athletes. Sports Health, 9, 168–173.
35.
CriscoJ.J., FioreR., BeckwithJ.G., ChuJ.J., BrolinsonP.G., DumaS., McAllisterT.W., DuhaimeA.C., and GreenwaldR.M. (2010). Frequency and location of head impact exposures in individual collegiate football players. J. Athl. Train., 45, 549–559.
36.
DumaS.M., ManoogianS.J., BussoneW.R., BrolinsonP.G., GoforthM.W., DonnenwerthJ.J., GreenwaldR.M., ChuJ.J., and CriscoJ.J. (2005). Analysis of real-time head accelerations in collegiate football players. Clin. J. Sport Med., 15, 3–8.
37.
ReynoldsB.B., PatrieJ., HenryE.J., GoodkinH.P., BroshekD.K., WintermarkM., and DruzgalT.J. (2015). Practice type effects on head impact in collegiate football. J. Neurosurg., 12, 501–510.
38.
BahramiN., SharmaD., RosenthalS., DavenportE.M., UrbanJ.E., WagnerB., JungY., VaughanC.G., GioiaG.A., StitzelJ.D., WhitlowC.T., and MaldjianJ.A. (2016). Subconcussive head impact exposure and white matter tract changes over a single season of youth football. Radiology, 281, 919–926.
39.
IliffJ.J., ChenM.J., PlogB.A., ZeppenfeldD.M., SolteroM., YangL., SinghI., DeaneR., and NedergaardM. (2014). Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J. Neurosci., 34, 16180–16193.
40.
PlogB.A., DashnawM.L., HitomiE., PengW., LiaoY., LouN., DeaneR., and NedergaardM. (2015). Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J. Neurosci., 35, 518–526.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
