Cerebrospinal fluid levels of neuroinflammatory biomarkers are increased in athletes with persistent post-concussive symptoms following sports-related concussion.
Biomarkers
Cerebrospinal fluid
Chemokines
Concussion
Cytokines
Neuroinflammation
Persisting post-concussive symptoms
Sport
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
17 Aug 2023
17 Aug 2023
Historique:
received:
17
05
2023
accepted:
29
07
2023
medline:
21
8
2023
pubmed:
18
8
2023
entrez:
17
8
2023
Statut:
epublish
Résumé
A sports-related concussion (SRC) is often caused by rapid head rotation at impact, leading to shearing and stretching of axons in the white matter and initiation of secondary inflammatory processes that may exacerbate the initial injury. We hypothesized that athletes with persistent post-concussive symptoms (PPCS) display signs of ongoing neuroinflammation, as reflected by altered profiles of cerebrospinal fluid (CSF) biomarkers, in turn relating to symptom severity. We recruited athletes with PPCS preventing sports participation as well as limiting work, school and/or social activities for ≥ 6 months for symptom rating using the Sport Concussion Assessment Tool, version 5 (SCAT-5) and for cognitive assessment using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Following a spinal tap, we analysed 27 CSF inflammatory biomarkers (pro-inflammatory chemokines and cytokine panels) by a multiplex immunoassay using antibodies as electrochemiluminescent labels to quantify concentrations in PPCS athletes, and in healthy age- and sex-matched controls exercising ≤ 2 times/week at low-to-moderate intensity. Thirty-six subjects were included, 24 athletes with PPCS and 12 controls. The SRC athletes had sustained a median of five concussions, the most recent at a median of 17 months prior to the investigation. CSF cytokines and chemokines levels were significantly increased in eight (IL-2, TNF-α, IL-15, TNF-β, VEGF, Eotaxin, IP-10, and TARC), significantly decreased in one (Eotaxin-3), and unaltered in 16 in SRC athletes when compared to controls, and two were un-detectable. The SRC athletes reported many and severe post-concussive symptoms on SCAT5, and 10 out of 24 athletes performed in the impaired range (Z < - 1.5) on cognitive testing. Individual biomarker concentrations did not strongly correlate with symptom rating or cognitive function. Limitations include evaluation at a single post-injury time point in relatively small cohorts, and no control group of concussed athletes without persisting symptoms was included. Based on CSF inflammatory marker profiling we find signs of ongoing neuroinflammation persisting months to years after the last SRC in athletes with persistent post-concussive symptoms. Since an ongoing inflammatory response may exacerbate the brain injury these results encourage studies of treatments targeting the post-injury inflammatory response in sports-related concussion.
Identifiants
pubmed: 37592277
doi: 10.1186/s12974-023-02864-0
pii: 10.1186/s12974-023-02864-0
pmc: PMC10433539
doi:
Substances chimiques
Cytokines
0
Biomarkers
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
189Subventions
Organisme : Swedish Brain Foundation
ID : FO2022-0154
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
McCrory P, Feddermann-Demont N, Dvorak J, et al. What is the definition of sports-related concussion: a systematic review. Br J Sports Med. 2017;51:877–87.
pubmed: 29098981
doi: 10.1136/bjsports-2016-097393
Vedantam A, Brennan J, Levin HS, et al. Early versus late profiles of inflammatory cytokines after mild traumatic brain injury and their association with neuropsychological outcomes. J Neurotrauma. 2021;38:53–62.
pubmed: 32600167
doi: 10.1089/neu.2019.6979
Schwab N, Grenier K, Hazrati LN. DNA repair deficiency and senescence in concussed professional athletes involved in contact sports. Acta Neuropathol Commun. 2019;7:182.
pubmed: 31727161
pmcid: 6857343
doi: 10.1186/s40478-019-0822-3
Tang-Schomer MD, Johnson VE, Baas PW, Stewart W, Smith DH. Partial interruption of axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic axonal injury. Exp Neurol. 2012;233:364–72.
pubmed: 22079153
doi: 10.1016/j.expneurol.2011.10.030
Patterson ZR, Holahan MR. Understanding the neuroinflammatory response following concussion to develop treatment strategies. Front Cell Neurosci. 2012;6:58.
pubmed: 23248582
pmcid: 3520152
doi: 10.3389/fncel.2012.00058
Batchelder BC, Krause BA, Seegmiller JG, Starkey CA. Gastrointestinal temperature increases and hypohydration exists after collegiate men’s ice hockey participation. J Strength Cond Res. 2010;24:68–73.
pubmed: 20042926
doi: 10.1519/JSC.0b013e3181c49114
Sakurai A, Atkins CM, Alonso OF, Bramlett HM, Dietrich WD. Mild hyperthermia worsens the neuropathological damage associated with mild traumatic brain injury in rats. J Neurotrauma. 2012;29:313–21.
pubmed: 22026555
pmcid: 3261791
doi: 10.1089/neu.2011.2152
Bonds BW, Hu P, Li Y, et al. Predictive value of hyperthermia and intracranial hypertension on neurological outcomes in patients with severe traumatic brain injury. Brain Inj. 2015;29:1642–7.
pubmed: 26479461
doi: 10.3109/02699052.2015.1075157
Tator CH, Davis HS, Dufort PA, et al. Postconcussion syndrome: demographics and predictors in 221 patients. J Neurosurg. 2016;125:1206–16.
pubmed: 26918481
doi: 10.3171/2015.6.JNS15664
Hiploylee C, Dufort PA, Davis HS, et al. Longitudinal study of postconcussion syndrome: not everyone recovers. J Neurotrauma. 2017;34:1511–23.
pubmed: 27784191
pmcid: 5397249
doi: 10.1089/neu.2016.4677
Shahim P, Tegner Y, Gustafsson B, et al. Neurochemical aftermath of repetitive mild traumatic brain injury. JAMA Neurol. 2016;73:1308–15.
pubmed: 27654934
doi: 10.1001/jamaneurol.2016.2038
Shahim P, Zetterberg H. Neurochemical markers of traumatic brain injury: relevance to acute diagnostics, disease monitoring, and neuropsychiatric outcome prediction. Biol Psychiatry. 2022;91:405–12.
pubmed: 34857362
doi: 10.1016/j.biopsych.2021.10.010
Johnson VE, Stewart W, Smith DH. Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans. Brain Pathol. 2012;22:142–9.
pubmed: 21714827
doi: 10.1111/j.1750-3639.2011.00513.x
Marklund N, Vedung F, Lubberink M, et al. Tau aggregation and increased neuroinflammation in athletes after sports-related concussions and in traumatic brain injury patients—a PET/MR study. Neuroimage Clin. 2021;30: 102665.
pubmed: 33894460
pmcid: 8091173
doi: 10.1016/j.nicl.2021.102665
Isung J, Granqvist M, Trepci A, et al. Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects. Sci Rep. 2021;11:1669.
pubmed: 33462306
pmcid: 7814004
doi: 10.1038/s41598-021-81306-4
Sport concussion assessment tool, 5th edn. Br J Sports Med. 2017;51:851–8.
Echemendia RJ, Meeuwisse W, McCrory P, et al. The Sport Concussion Assessment Tool 5th Edition (SCAT5): background and rationale. Br J Sports Med. 2017;51:848–50.
pubmed: 28446453
Randolph C. Repeatable battery for the assessment of neuropsychological status—RBANS. Stockholm: Pearson Assessment; 2013.
Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20:310–9.
pubmed: 9845158
doi: 10.1076/jcen.20.3.310.823
McKay C, Casey JE, Wertheimer J, Fichtenberg NL. Reliability and validity of the RBANS in a traumatic brain injured sample. Arch Clin Neuropsychol. 2007;22:91–8.
pubmed: 17141467
doi: 10.1016/j.acn.2006.11.003
Pachet AK. Construct validity of the Repeatable Battery of Neuropsychological Status (RBANS) with acquired brain injury patients. Clin Neuropsychol. 2007;21:286–93.
pubmed: 17455019
doi: 10.1080/13854040500376823
Feng C, Wang H, Lu N, et al. Log-transformation and its implications for data analysis. Shanghai Arch Psychiatry. 2014;26:105–9.
pubmed: 25092958
pmcid: 4120293
Petersen RC, Morris JC. Mild cognitive impairment as a clinical entity and treatment target. Arch Neurol. 2005;62:1160–3; discussion 7.
pubmed: 16009779
doi: 10.1001/archneur.62.7.1160
Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J. Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron. 2017;95:1246–65.
pubmed: 28910616
pmcid: 5678753
doi: 10.1016/j.neuron.2017.07.010
Engel S, Schluesener H, Mittelbronn M, et al. Dynamics of microglial activation after human traumatic brain injury are revealed by delayed expression of macrophage-related proteins MRP8 and MRP14. Acta Neuropathol. 2000;100:313–22.
pubmed: 10965802
doi: 10.1007/s004019900172
Witcher KG, Bray CE, Chunchai T, et al. Traumatic brain injury causes chronic cortical inflammation and neuronal dysfunction mediated by microglia. J Neurosci. 2021;41:1597–616.
pubmed: 33452227
pmcid: 7896020
doi: 10.1523/JNEUROSCI.2469-20.2020
Johnson VE, Stewart JE, Begbie FD, et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain. 2013;136:28–42.
pubmed: 23365092
pmcid: 3562078
doi: 10.1093/brain/aws322
Ramlackhansingh AF, Brooks DJ, Greenwood RJ, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 2011;70:374–83.
pubmed: 21710619
doi: 10.1002/ana.22455
Jacquens A, Needham EJ, Zanier ER, Degos V, Gressens P, Menon D. Neuro-inflammation modulation and post-traumatic brain injury lesions: from bench to bed-side. Int J Mol Sci. 2022;23(19):11193.
pubmed: 36232495
pmcid: 9570205
doi: 10.3390/ijms231911193
Goldstein LE, Fisher AM, Tagge CA, et al. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med. 2012;4:134ra60.
pubmed: 22593173
pmcid: 3739428
Yang SH, Gustafson J, Gangidine M, et al. A murine model of mild traumatic brain injury exhibiting cognitive and motor deficits. J Surg Res. 2013;184:981–8.
pubmed: 23622728
pmcid: 4073786
doi: 10.1016/j.jss.2013.03.075
Yang SH, Gangidine M, Pritts TA, Goodman MD, Lentsch AB. Interleukin 6 mediates neuroinflammation and motor coordination deficits after mild traumatic brain injury and brief hypoxia in mice. Shock. 2013;40:471–5.
pubmed: 24088994
pmcid: 4218737
doi: 10.1097/SHK.0000000000000037
Drieu A, Lanquetin A, Prunotto P, et al. Persistent neuroinflammation and behavioural deficits after single mild traumatic brain injury. J Cereb Blood Flow Metab. 2022;42:2216–29.
pubmed: 35945692
pmcid: 9670002
doi: 10.1177/0271678X221119288
Mouzon BC, Bachmeier C, Ferro A, et al. Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model. Ann Neurol. 2014;75:241–54.
pubmed: 24243523
doi: 10.1002/ana.24064
Mouzon BC, Bachmeier C, Ojo JO, et al. Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury. Ann Clin Transl Neurol. 2018;5:64–80.
pubmed: 29376093
doi: 10.1002/acn3.510
Shultz SR, Bao F, Omana V, et al. Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioral impairments, neuroinflammation, and cortical loss in an animal model of repeated concussion. J Neurotrauma. 2012;29:281–94.
pubmed: 21933013
doi: 10.1089/neu.2011.2123
Webster KM, Wright DK, Sun M, et al. Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury. J Neuroinflamm. 2015;12:238.
doi: 10.1186/s12974-015-0457-7
Huie JR, Diaz-Arrastia R, Yue JK, et al. Testing a multivariate proteomic panel for traumatic brain injury biomarker discovery: a TRACK-TBI pilot study. J Neurotrauma. 2019;36:100–10.
pubmed: 30084741
doi: 10.1089/neu.2017.5449
Meier TB, Huber DL, Bohorquez-Montoya L, et al. A prospective study of acute blood-based biomarkers for sport-related concussion. Ann Neurol. 2020;87:907–20.
pubmed: 32215965
pmcid: 7477798
doi: 10.1002/ana.25725
Chaban V, Clarke GJB, Skandsen T, et al. Systemic inflammation persists the first year after mild traumatic brain injury: results from the prospective trondheim mild traumatic brain injury study. J Neurotrauma. 2020;37:2120–30.
pubmed: 32326805
pmcid: 7502683
doi: 10.1089/neu.2019.6963
Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab. 2011;31:658–70.
pubmed: 20717122
doi: 10.1038/jcbfm.2010.142
Tobieson L, Gard A, Ruscher K, Marklund N. Intracerebral proinflammatory cytokine increase in surgically evacuated intracerebral hemorrhage: a microdialysis study. Neurocrit Care. 2022;36:876–87.
pubmed: 34850333
doi: 10.1007/s12028-021-01389-9
Coughlin JM, Wang Y, Munro CA, et al. Neuroinflammation and brain atrophy in former NFL players: an in vivo multimodal imaging pilot study. Neurobiol Dis. 2015;74:58–65.
pubmed: 25447235
doi: 10.1016/j.nbd.2014.10.019
Coughlin JM, Wang Y, Minn I, et al. Imaging of glial cell activation and white matter integrity in brains of active and recently retired national football league players. JAMA Neurol. 2017;74:67–74.
pubmed: 27893897
pmcid: 5504689
doi: 10.1001/jamaneurol.2016.3764
Bignami A, Eng LF, Dahl D, Uyeda CT. Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence. Brain Res. 1972;43:429–35.
pubmed: 4559710
doi: 10.1016/0006-8993(72)90398-8
McCrea M, Broglio SP, McAllister TW, et al. Association of blood biomarkers with acute sport-related concussion in collegiate athletes: findings from the NCAA and Department of Defense CARE Consortium. JAMA Netw Open. 2020;3: e1919771.
pubmed: 31977061
pmcid: 6991302
doi: 10.1001/jamanetworkopen.2019.19771
Shahim P, Politis A, van der Merwe A, et al. Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI. Neurology. 2020;95:e623–36.
pubmed: 32641529
pmcid: 7455355
doi: 10.1212/WNL.0000000000009985
Cherry JD, Tripodis Y, Alvarez VE, et al. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta Neuropathol Commun. 2016;4:112.
pubmed: 27793189
pmcid: 5084333
doi: 10.1186/s40478-016-0382-8
Collins-Praino LE, Arulsamy A, Katharesan V, Corrigan F. The effect of an acute systemic inflammatory insult on the chronic effects of a single mild traumatic brain injury. Behav Brain Res. 2018;336:22–31.
pubmed: 28855139
doi: 10.1016/j.bbr.2017.08.035
Holleran L, Kim JH, Gangolli M, et al. Axonal disruption in white matter underlying cortical sulcus tau pathology in chronic traumatic encephalopathy. Acta Neuropathol. 2017;133:367–80.
pubmed: 28214960
doi: 10.1007/s00401-017-1686-x
Cavaillon JM. Pro- versus anti-inflammatory cytokines: myth or reality. Cell Mol Biol (Noisy-le-grand). 2001;47:695–702.
pubmed: 11502077
Di Battista AP, Rhind SG, Richards D, et al. Altered blood biomarker profiles in athletes with a history of repetitive head impacts. PLoS ONE. 2016;11: e0159929.
pubmed: 27458972
pmcid: 4961456
doi: 10.1371/journal.pone.0159929
Di Battista AP, Churchill N, Schweizer TA, et al. Blood biomarkers are associated with brain function and blood flow following sport concussion. J Neuroimmunol. 2018;319:1–8.
pubmed: 29685283
doi: 10.1016/j.jneuroim.2018.03.002
O’Brien WT, Symons GF, Bain J, et al. Elevated serum interleukin-1beta levels in male, but not female, collision sport athletes with a concussion history. J Neurotrauma. 2021;38:1350–7.
pubmed: 33308001
doi: 10.1089/neu.2020.7479
Perneger TV. What’s wrong with Bonferroni adjustments. BMJ. 1998;316:1236–8.
pubmed: 9553006
pmcid: 1112991
doi: 10.1136/bmj.316.7139.1236