Skip to main content

Mechanical disruption of the blood–brain barrier following experimental concussion

Acta Neuropathologica volume 135, pages 711–726 (2018)Cite this article

Abstract

Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood–brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion findings through comparisons with pathological changes in human severe TBI, where post-mortem examinations are possible. At 6–72 h post-injury in swine, we observed multifocal disruption of the BBB, demonstrated by extravasation of serum proteins, fibrinogen and immunoglobulin-G, in the absence of hemorrhage or other focal pathology. BBB disruption was observed in a stereotyped distribution consistent with biomechanical insult. Specifically, extravasated serum proteins were frequently observed at interfaces between regions of tissue with differing material properties, including the gray–white boundary, periventricular and subpial regions. In addition, there was substantial overlap of BBB disruption with regions of axonal pathology in the white matter. Acute perivascular cellular uptake of blood-borne proteins was observed to be prominent in astrocytes (GFAP-positive) and neurons (MAP-2-positive), but not microglia (IBA1-positive). Parallel examination of human severe TBI revealed similar patterns of serum extravasation and glial uptake of serum proteins, but to a much greater extent than in the swine model, attributed to the higher injury severity. These data suggest that BBB disruption represents a new and important pathological feature of concussion.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellan DR (1989) Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology 15:49–59

    CAS  Article  PubMed  Google Scholar 

  2. Adams JH, Graham DI, Gennarelli TA, Maxwell WL (1991) Diffuse axonal injury in non-missile head injury. J Neurol Neurosurg Psychiatry 54:481–483

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Adams JH, Graham DI, Murray LS, Scott G (1982) Diffuse axonal injury due to nonmissile head injury in humans: an analysis of 45 cases. Ann Neurol 12:557–563

    CAS  Article  PubMed  Google Scholar 

  4. Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K (2007) The fibrin-derived γ377–395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med 204:571–582. https://doi.org/10.1084/jem.20061931

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Adams RA, Passino M, Sachs BD, Nuriel T, Akassoglou K (2004) Fibrin mechanisms and functions in nervous system pathology. Mol Interv 4:163–176. https://doi.org/10.1124/mi.4.3.6

    CAS  PubMed  Google Scholar 

  6. Akassoglou K, Adams RA, Bauer J, Mercado P, Tseveleki V, Lassmann H, Probert L, Strickland S (2004) Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis. Proc Natl Acad Sci USA 101:6698–6703. https://doi.org/10.1073/pnas.0303859101

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Alvarez JI, Saint-Laurent O, Godschalk A, Terouz S, Briels C, Larouche S, Bourbonniere L, Larochelle C, Prat A (2015) Focal disturbances in the blood–brain barrier are associated with formation of neuroinflammatory lesions. Neurobiol Dis 74:14–24. https://doi.org/10.1016/j.nbd.2014.09.016

    CAS  Article  PubMed  Google Scholar 

  8. Bain AC, Meaney DF (2000) Tissue-level thresholds for axonal damage in an experimental model of central nervous system white matter injury. J Biomech Eng 122:615–622

    CAS  Article  PubMed  Google Scholar 

  9. Baldwin SA, Fugaccia I, Brown DR, Brown LV, Scheff SW (1996) Blood–brain barrier breach following cortical contusion in the rat. J Neurosurg 85:476–481. https://doi.org/10.3171/jns.1996.85.3.0476

    CAS  Article  PubMed  Google Scholar 

  10. Barzo P, Marmarou A, Fatouros P, Corwin F, Dunbar J (1996) Magnetic resonance imaging—monitored acute blood–brain barrier changes in experimental traumatic brain injury. J Neurosurg 85:1113–1121. https://doi.org/10.3171/jns.1996.85.6.1113

    CAS  Article  PubMed  Google Scholar 

  11. Bazarian JJ, McClung J, Shah MN, Cheng YT, Flesher W, Kraus J (2005) Mild traumatic brain injury in the United States, 1998–2000. Brain Inj 19:85–91

    Article  PubMed  Google Scholar 

  12. Bazarian JJ, Zhong J, Blyth B, Zhu T, Kavcic V, Peterson D (2007) Diffusion tensor imaging detects clinically important axonal damage after mild traumatic brain injury: a pilot study. J Neurotrauma 24:1447–1459. https://doi.org/10.1089/neu.2007.0241

    Article  PubMed  Google Scholar 

  13. Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ (1994) Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet 344:1055–1056

    CAS  Article  PubMed  Google Scholar 

  14. Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ (1995) Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. J Neurotrauma 12:565–572

    CAS  Article  PubMed  Google Scholar 

  15. Bridges LR, Andoh J, Lawrence AJ, Khoong CH, Poon WW, Esiri MM, Markus HS, Hainsworth AH (2014) Blood–brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people. J Neuropathol Exp Neurol 73:1026–1033. https://doi.org/10.1097/NEN.0000000000000124

    Article  PubMed  PubMed Central  Google Scholar 

  16. Brown H, Hien TT, Day N, Mai NT, Chuong LV, Chau TT, Loc PP, Phu NH, Bethell D, Farrar J et al (1999) Evidence of blood–brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol 25:331–340

    CAS  Article  PubMed  Google Scholar 

  17. Browne KD, Chen XH, Meaney DF, Smith DH (2011) Mild traumatic brain injury and diffuse axonal injury in swine. J Neurotrauma 28:1747–1755. https://doi.org/10.1089/neu.2011.1913

    Article  PubMed  PubMed Central  Google Scholar 

  18. Coronado VG, Haileyesus T, Cheng TA, Bell JM, Haarbauer-Krupa J, Lionbarger MR, Flores-Herrera J, McGuire LC, Gilchrist J (2015) Trends in sports- and recreation-related traumatic brain injuries treated in US emergency departments: the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) 2001–2012. J Head Trauma Rehabil 30:185–197. https://doi.org/10.1097/HTR.0000000000000156

    Article  PubMed  Google Scholar 

  19. Cullen DK, Harris JP, Browne KD, Wolf JA, Duda JE, Meaney DF, Margulies SS, Smith DH (2016) A porcine model of traumatic brain injury via head rotational acceleration. Methods Mol Biol 1462:289–324. https://doi.org/10.1007/978-1-4939-3816-2_17

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Dallasta LM, Pisarov LA, Esplen JE, Werley JV, Moses AV, Nelson JA, Achim CL (1999) Blood–brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1915–1927. https://doi.org/10.1016/S0002-9440(10)65511-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Eierud C, Craddock RC, Fletcher S, Aulakh M, King-Casas B, Kuehl D, LaConte SM (2014) Neuroimaging after mild traumatic brain injury: review and meta-analysis. NeuroImage Clin 4:283–294. https://doi.org/10.1016/j.nicl.2013.12.009

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gabler LF, Crandall JR, Panzer MB (2016) Assessment of kinematic brain injury metrics for predicting strain responses in diverse automotive impact conditions. Ann Biomed Eng 44:3705–3718. https://doi.org/10.1007/s10439-016-1697-0

    Article  PubMed  Google Scholar 

  23. Geddes JF, Vowles GH, Beer TW, Ellison DW (1997) The diagnosis of diffuse axonal injury: implications for forensic practice. Neuropathol Appl Neurobiol 23:339–347

    CAS  Article  PubMed  Google Scholar 

  24. Geddes JF, Vowles GH, Nicoll JA, Revesz T (1999) Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol 98:171–178

    CAS  Article  PubMed  Google Scholar 

  25. Geddes JF, Whitwell HL, Graham DI (2000) Traumatic axonal injury: practical issues for diagnosis in medicolegal cases. Neuropathol Appl Neurobiol 26:105–116

    CAS  Article  PubMed  Google Scholar 

  26. Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP (1982) Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 12:564–574. https://doi.org/10.1002/ana.410120611

    CAS  Article  PubMed  Google Scholar 

  27. Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW (1993) Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 160:139–144

    CAS  Article  PubMed  Google Scholar 

  28. Gentleman SM, Roberts GW, Gennarelli TA, Maxwell WL, Adams JH, Kerr S, Graham DI (1995) Axonal injury: a universal consequence of fatal closed head injury? Acta Neuropathol 89:537–543

    CAS  Article  PubMed  Google Scholar 

  29. Giordano C, Kleiven S (2014) Evaluation of axonal strain as a predictor for mild traumatic brain injuries using finite element modeling. Stapp Car Crash J 58:29–61

    PubMed  Google Scholar 

  30. Graham DI, Gennarelli TA, McIntosh TK (2002) Greenfield’s neuropathology. Arnold, ‎London, UK

    Google Scholar 

  31. Graham DI, Gentleman SM, Lynch A, Roberts GW (1995) Distribution of beta-amyloid protein in the brain following severe head injury. Neuropathol Appl Neurobiol 21:27–34

    CAS  Article  PubMed  Google Scholar 

  32. Graham DI, Smith C, Reichard R, Leclercq PD, Gentleman SM (2004) Trials and tribulations of using beta-amyloid precursor protein immunohistochemistry to evaluate traumatic brain injury in adults. Forensic Sci Int 146:89–96. https://doi.org/10.1016/S0379-0738(03)00274-3

    CAS  Article  PubMed  Google Scholar 

  33. Hay J, Johnson VE, Smith DH, Stewart W (2016) Chronic traumatic encephalopathy: the neuropathological legacy of traumatic brain injury. Annu Rev Pathol 11:21–45. https://doi.org/10.1146/annurev-pathol-012615-044116

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Hay JR, Johnson VE, Young AM, Smith DH, Stewart W (2015) Blood–brain barrier disruption is an early event that may persist for many years after traumatic brain injury in humans. J Neuropathol Exp Neurol 74:1147–1157. https://doi.org/10.1097/NEN.0000000000000261

    CAS  PubMed  Google Scholar 

  35. Hayashi T, Ago K, Ago M, Ogata M (2009) Two patterns of beta-amyloid precursor protein (APP) immunoreactivity in cases of blunt head injury. Leg Med (Tokyo) 11(Suppl 1):S171–S173. https://doi.org/10.1016/j.legalmed.2009.01.076

    Article  Google Scholar 

  36. Holbourn AHS (1945) Mechanics of brain injuries. Br Med Bull 3:147–149

    Article  Google Scholar 

  37. Holbourn AHS (1943) Mechanics of head injury. Lancet 242:438–441

    Article  Google Scholar 

  38. Hsiao TW, Swarup VP, Kuberan B, Tresco PA, Hlady V (2013) Astrocytes specifically remove surface-adsorbed fibrinogen and locally express chondroitin sulfate proteoglycans. Acta Biomater 9:7200–7208. https://doi.org/10.1016/j.actbio.2013.02.047

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Ibrahim NG, Natesh R, Szczesny SE, Ryall K, Eucker SA, Coats B, Margulies SS (2010) In situ deformations in the immature brain during rapid rotations. J Biomech Eng 132:044501. https://doi.org/10.1115/1.4000956

    Article  PubMed  Google Scholar 

  40. Ji S, Zhao W, Ford JC, Beckwith JG, Bolander RP, Greenwald RM, Flashman LA, Paulsen KD, McAllister TW (2015) Group-wise evaluation and comparison of white matter fiber strain and maximum principal strain in sports-related concussion. J Neurotrauma 32:441–454. https://doi.org/10.1089/neu.2013.3268

    Article  PubMed  PubMed Central  Google Scholar 

  41. Johnson VE, Meaney DF, Cullen DK, Smith DH (2015) Animal models of traumatic brain injury. Handb Clin Neurol 127:115–128. https://doi.org/10.1016/B978-0-444-52892-6.00008-8

    Article  PubMed  PubMed Central  Google Scholar 

  42. Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W (2013) Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136:28–42

    Article  PubMed  PubMed Central  Google Scholar 

  43. Johnson VE, Stewart W, Smith DH (2013) Axonal pathology in traumatic brain injury. Exp Neurol 246:35–43. https://doi.org/10.1016/j.expneurol.2012.01.013

    CAS  Article  PubMed  Google Scholar 

  44. Johnson VE, Stewart W, Weber MT, Cullen DK, Siman R, Smith DH (2016) SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury. Acta Neuropathol 131:115–135. https://doi.org/10.1007/s00401-015-1506-0

    CAS  Article  PubMed  Google Scholar 

  45. Kirk J, Plumb J, Mirakhur M, McQuaid S (2003) Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood–brain barrier leakage and active demyelination. J Pathol 201:319–327. https://doi.org/10.1002/path.1434

    Article  PubMed  Google Scholar 

  46. Kovacs GG, Robinson JL, Xie SX, Lee EB, Grossman M, Wolk DA, Irwin DJ, Weintraub D, Kim CF, Schuck T et al (2017) Evaluating the patterns of aging-related tau astrogliopathy unravels novel insights into brain aging and neurodegenerative diseases. J Neuropathol Exp Neurol 76:270–288. https://doi.org/10.1093/jnen/nlx007

    Article  PubMed  Google Scholar 

  47. Kraft RH, McKee PJ, Dagro AM, Grafton ST (2012) Combining the finite element method with structural connectome-based analysis for modeling neurotrauma: connectome neurotrauma mechanics. PLoS Comput Biol 8:e1002619. https://doi.org/10.1371/journal.pcbi.1002619

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Kwon EE, Prineas JW (1994) Blood–brain barrier abnormalities in longstanding multiple sclerosis lesions. An immunohistochemical study. J Neuropathol Exp Neurol 53:625–636

    CAS  Article  PubMed  Google Scholar 

  49. Leclercq PD, McKenzie JE, Graham DI, Gentleman SM (2001) Axonal injury is accentuated in the caudal corpus callosum of head-injured patients. J Neurotrauma 18:1–9

    CAS  Article  PubMed  Google Scholar 

  50. Lee P, Kim J, Williams R, Sandhir R, Gregory E, Brooks WM, Berman NE (2012) Effects of aging on blood–brain barrier and matrix metalloproteases following controlled cortical impact in mice. Exp Neurol 234:50–61. https://doi.org/10.1016/j.expneurol.2011.12.016

    CAS  Article  PubMed  Google Scholar 

  51. Levin HS, Diaz-Arrastia RR (2015) Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol 14:506–517. https://doi.org/10.1016/S1474-4422(15)00002-2

    Article  PubMed  Google Scholar 

  52. Liu HM, Atack JR, Rapoport SI (1989) Immunohistochemical localization of intracellular plasma proteins in the human central nervous system. Acta Neuropathol 78:16–21

    CAS  Article  PubMed  Google Scholar 

  53. Liu JY, Thom M, Catarino CB, Martinian L, Figarella-Branger D, Bartolomei F, Koepp M, Sisodiya SM (2012) Neuropathology of the blood–brain barrier and pharmaco-resistance in human epilepsy. Brain 135:3115–3133. https://doi.org/10.1093/brain/aws147

    Article  PubMed  Google Scholar 

  54. Margulies SS, Thibault LE, Gennarelli TA (1990) Physical model simulations of brain injury in the primate. J Biomech 23:823–836. https://doi.org/10.1016/0021-9290(90)90029-3

    CAS  Article  PubMed  Google Scholar 

  55. Mayer AR, Ling J, Mannell MV, Gasparovic C, Phillips JP, Doezema D, Reichard R, Yeo RA (2010) A prospective diffusion tensor imaging study in mild traumatic brain injury. Neurology 74:643–650. https://doi.org/10.1212/WNL.0b013e3181d0ccdd

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W et al (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:75–86. https://doi.org/10.1007/s00401-015-1515-z

    CAS  Article  PubMed  Google Scholar 

  57. McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64. https://doi.org/10.1093/brain/aws307

    Article  PubMed  Google Scholar 

  58. Meaney DF, Smith DH, Shreiber DI, Bain AC, Miller RT, Ross DT, Gennarelli TA (1995) Biomechanical analysis of experimental diffuse axonal injury. J Neurotrauma 12:689–694

    CAS  Article  PubMed  Google Scholar 

  59. Miles L, Grossman RI, Johnson G, Babb JS, Diller L, Inglese M (2008) Short-term DTI predictors of cognitive dysfunction in mild traumatic brain injury. Brain Inj 22:115–122. https://doi.org/10.1080/02699050801888816

    Article  PubMed  Google Scholar 

  60. Mori T, Wang X, Aoki T, Lo EH (2002) Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury. J Neurotrauma 19:1411–1419. https://doi.org/10.1089/089771502320914642

    Article  PubMed  Google Scholar 

  61. Nguyen R, Fiest KM, McChesney J, Kwon CS, Jette N, Frolkis AD, Atta C, Mah S, Dhaliwal H, Reid A et al (2016) The international incidence of traumatic brain injury: a systematic review and meta-analysis. Can J Neurol Sci 43:774–785. https://doi.org/10.1017/cjn.2016.290

    Article  PubMed  Google Scholar 

  62. Niogi SN, Mukherjee P, Ghajar J, Johnson C, Kolster RA, Sarkar R, Lee H, Meeker M, Zimmerman RD, Manley GT et al (2008) Extent of microstructural white matter injury in postconcussive syndrome correlates with impaired cognitive reaction time: a 3T diffusion tensor imaging study of mild traumatic brain injury. AJNR Am J Neuroradiol 29:967–973. https://doi.org/10.3174/ajnr.A0970

    CAS  Article  PubMed  Google Scholar 

  63. Ommaya AK Yarnell P, Hirsch AE, Harris EH (1967) Scaling of experimental data on cerebral concussion in sub-human primates to concussive thresholds in man. SAE Technical Paper. In: proceedings of the 11th Stapp car crash conference, Warrendale, PA, pp 73–80

  64. Patton DA, McIntosh AS, Kleiven S (2015) The biomechanical determinants of concussion: finite element simulations to investigate tissue-level predictors of injury during sporting impacts to the unprotected head. J Appl Biomech 31:264–268. https://doi.org/10.1123/jab.2014-0223

    Article  PubMed  Google Scholar 

  65. Petito CK, Cash KS (1992) Blood–brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol 32:658–666. https://doi.org/10.1002/ana.410320509

    CAS  Article  PubMed  Google Scholar 

  66. Povlishock JT, Becker DP, Miller JD, Jenkins LW, Dietrich WD (1979) The morphopathologic substrates of concussion? Acta Neuropathol 47:1–11

    CAS  Article  PubMed  Google Scholar 

  67. Povlishock JT, Becker DP, Sullivan HG, Miller JD (1978) Vascular permeability alterations to horseradish peroxidase in experimental brain injury. Brain Res 153:223–239

    CAS  Article  PubMed  Google Scholar 

  68. Rabinowitz AR, Li X, McCauley SR, Wilde EA, Barnes A, Hanten G, Mendez D, McCarthy JJ, Levin HS (2015) Prevalence and predictors of poor recovery from mild traumatic brain injury. J Neurotrauma 32:1488–1496. https://doi.org/10.1089/neu.2014.3555

    Article  PubMed  PubMed Central  Google Scholar 

  69. Reichard RR, Smith C, Graham DI (2005) The significance of beta-APP immunoreactivity in forensic practice. Neuropathol Appl Neurobiol 31:304–313. https://doi.org/10.1111/j.1365-2990.2005.00645.x

    CAS  Article  PubMed  Google Scholar 

  70. Roe C, Sveen U, Alvsaker K, Bautz-Holter E (2009) Post-concussion symptoms after mild traumatic brain injury: influence of demographic factors and injury severity in a 1-year cohort study. Disabil Rehabil 31:1235–1243. https://doi.org/10.1080/09638280802532720

    Article  PubMed  Google Scholar 

  71. Ross DT, Meaney DF, Sabol MK, Smith DH, Gennarelli TA (1994) Distribution of forebrain diffuse axonal injury following inertial closed head injury in miniature swine. Exp Neurol 126:291–299. https://doi.org/10.1006/exnr.1994.1067

    CAS  Article  PubMed  Google Scholar 

  72. Ryu JK, McLarnon JG (2009) A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain. J Cell Mol Med 13:2911–2925. https://doi.org/10.1111/j.1582-4934.2008.00434.x

    CAS  Article  PubMed  Google Scholar 

  73. Ryu JK, Petersen MA, Murray SG, Baeten KM, Meyer-Franke A, Chan JP, Vagena E, Bedard C, Machado MR, Rios Coronado PE et al (2015) Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat Commun 6:8164. https://doi.org/10.1038/ncomms9164

    Article  PubMed  PubMed Central  Google Scholar 

  74. Schachtrup C, Lu P, Jones LL, Lee JK, Lu J, Sachs BD, Zheng B, Akassoglou K (2007) Fibrinogen inhibits neurite outgrowth via beta 3 integrin-mediated phosphorylation of the EGF receptor. Proc Natl Acad Sci USA 104:11814–11819. https://doi.org/10.1073/pnas.0704045104

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Schachtrup C, Ryu JK, Helmrick MJ, Vagena E, Galanakis DK, Degen JL, Margolis RU, Akassoglou K (2010) Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage. J Neurosci 30:5843–5854. https://doi.org/10.1523/JNEUROSCI.0137-10.2010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Shahim P, Tegner Y, Wilson DH, Randall J, Skillback T, Pazooki D, Kallberg B, Blennow K, Zetterberg H (2014) Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol 71:684–692. https://doi.org/10.1001/jamaneurol.2014.367

    Article  PubMed  Google Scholar 

  77. Sherriff FE, Bridges LR, Sivaloganathan S (1994) Early detection of axonal injury after human head trauma using immunocytochemistry for beta-amyloid precursor protein. Acta Neuropathol (Berl) 87:55–62

    CAS  Article  Google Scholar 

  78. Shigemori Y, Katayama Y, Mori T, Maeda T, Kawamata T (2006) Matrix metalloproteinase-9 is associated with blood–brain barrier opening and brain edema formation after cortical contusion in rats. Acta Neurochir Suppl 96:130–133

    CAS  Article  PubMed  Google Scholar 

  79. Shreiber D, Bain, A, Meaney D (1997) In vivo thresholds for mechanical injury to the blood–brain barrier. SAE Technical Paper 973335. https://doi.org/10.4271/973335

  80. Siman R, Giovannone N, Hanten G, Wilde EA, McCauley SR, Hunter JV, Li X, Levin HS, Smith DH (2013) Evidence that the blood biomarker SNTF predicts brain imaging changes and persistent cognitive dysfunction in mild TBI patients. Front Neurol 4:190. https://doi.org/10.3389/fneur.2013.00190

    Article  PubMed  PubMed Central  Google Scholar 

  81. Siman R, Shahim P, Tegner Y, Blennow K, Zetterberg H, Smith DH (2015) Serum SNTF increases in concussed professional ice hockey players and relates to the severity of postconcussion symptoms. J Neurotrauma. https://doi.org/10.1089/neu.2014.3698 (in press)

    PubMed  PubMed Central  Google Scholar 

  82. Smith DH, Chen XH, Xu BN, McIntosh TK, Gennarelli TA, Meaney DF (1997) Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol Exp Neurol 56:822–834

    CAS  Article  PubMed  Google Scholar 

  83. Smith DH, Johnson VE, Stewart W (2013) Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol 9:211–221

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Smith DH, Meaney DF (2000) Axonal damage in traumatic brain injury. Neuroscientist 6:483–495

    Article  Google Scholar 

  85. Smith DH, Nonaka M, Miller R, Leoni M, Chen XH, Alsop D, Meaney DF (2000) Immediate coma following inertial brain injury dependent on axonal damage in the brainstem. J Neurosurg 93:315–322. https://doi.org/10.3171/jns.2000.93.2.0315

    CAS  Article  PubMed  Google Scholar 

  86. Smith DH, Wolf JA, Lusardi TA, Lee VM, Meaney DF (1999) High tolerance and delayed elastic response of cultured axons to dynamic stretch injury. J Neurosci 19:4263–4269

    CAS  Article  PubMed  Google Scholar 

  87. Strich SJ (1961) Sharing of the nerve fibers as a cause of brain damage due to head injury: a pathological study of 20 cases. Lancet 278:443–448

    Article  Google Scholar 

  88. Tang-Schomer MD, Johnson VE, Baas PW, Stewart W, Smith DH (2012) Partial interruption of axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic axonal injury. Exp Neurol 233:364–372. https://doi.org/10.1016/j.expneurol.2011.10.030

    Article  PubMed  Google Scholar 

  89. Thibault L, Gennarelli, TA, Margulies SS, et al (1990) The strain dependent pathophysiological consequences of inertial loading on central nervous system tissue. In: proceedings of the international conference on the Biomechanics Of Impact Lyon, France, pp 191–202

  90. Tomimoto H, Akiguchi I, Suenaga T, Nishimura M, Wakita H, Nakamura S, Kimura J (1996) Alterations of the blood–brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer’s disease patients. Stroke 27:2069–2074

    CAS  Article  PubMed  Google Scholar 

  91. Veksler R, Shelef I, Friedman A (2014) Blood–brain barrier imaging in human neuropathologies. Arch Med Res 45:646–652. https://doi.org/10.1016/j.arcmed.2014.11.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Viggars AP, Wharton SB, Simpson JE, Matthews FE, Brayne C, Savva GM, Garwood C, Drew D, Shaw PJ, Ince PG (2011) Alterations in the blood–brain barrier in ageing cerebral cortex in relationship to Alzheimer-type pathology: a study in the MRC-CFAS population neuropathology cohort. Neurosci Lett 505:25–30. https://doi.org/10.1016/j.neulet.2011.09.049

    CAS  Article  PubMed  Google Scholar 

  93. Weissberg I, Veksler R, Kamintsky L, Saar-Ashkenazy R, Milikovsky DZ, Shelef I, Friedman A (2014) Imaging blood–brain barrier dysfunction in football players. JAMA Neurol 71:1453–1455. https://doi.org/10.1001/jamaneurol.2014.2682

    Article  PubMed  Google Scholar 

  94. Wilde EA, McCauley SR, Hunter JV, Bigler ED, Chu Z, Wang ZJ, Hanten GR, Troyanskaya M, Yallampalli R, Li X et al (2008) Diffusion tensor imaging of acute mild traumatic brain injury in adolescents. Neurology 70:948–955. https://doi.org/10.1212/01.wnl.0000305961.68029.54

    CAS  Article  PubMed  Google Scholar 

  95. Yallampalli R, Wilde EA, Bigler ED, McCauley SR, Hanten G, Troyanskaya M, Hunter JV, Chu Z, Li X, Levin HS (2013) Acute white matter differences in the fornix following mild traumatic brain injury using diffusion tensor imaging. J Neuroimaging Off J Am Soc Neuroimaging 23:224–227. https://doi.org/10.1111/j.1552-6569.2010.00537.x

    Article  Google Scholar 

  96. Zhang H, Adwanikar H, Werb Z, Noble-Haeusslein LJ (2010) Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes. Neuroscientist 16:156–170. https://doi.org/10.1177/1073858409355830

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Kathryn Wofford for assistant with kinematic measurements. Research reported in this publication was supported by the Department of Defense Grant W81XWH-13-1-0052, and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers R01NS092398, R01NS094003 and R01NS038104, and the Department of Veterans Affairs under Merit Review number I01RX001097.

Author information

Affiliations

  1. Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA, 19104, USA

    Victoria E. Johnson, Maura T. Weber, D. Kacy Cullen & Douglas H. Smith

  2. The Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Rui Xiao

  3. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA

    D. Kacy Cullen & David F. Meaney

  4. Department of Neuropathology, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK

    William Stewart

  5. Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, G12 8QQ, UK

    William Stewart

  6. Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 19104, USA

    D. Kacy Cullen

Authors
  1. Victoria E. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maura T. Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Kacy Cullen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David F. Meaney
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Douglas H. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas H. Smith.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Additional information

The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Defense, National Institutes of Health, or Department of Veterans Affairs.

Electronic supplementary material

Below is the link to the electronic supplementary material.

401_2018_1824_MOESM1_ESM.tif

IgG Extravasation and Cellular Uptake Following Experimental Concussion. IgG extravasation was observed in a similar pattern and distribution to FBG shown at (a) the inferior aspect of the lateral ventricle and (b) a penetrating vessel at the cortical surface. (c) Cellular uptake of IgG was observed including cells with the morphological appearance of glia at the depth of a cortical sulcus and (d) cortical neurons. (e) Astrocytic (arrowhead) immunoreactivity for IgG was confirmed using triple labeling immunofluorescence with markers IgG (green), IBA-1 (red) and GFAP (purple). Note a cell with the morphological appearance of a neuron with no co-localization with glial marker is also shown (arrow). (f) Neuronal uptake was further confirmed with markers IgG (green) and MAP-2 (red) demonstrating co-localization. (g-i) Similar patterns of IgG (green) and FBG (red) extravasation were observed in double immunofluorescent labeling studies. Scale bars: (a-d) 25 μm, (e-i) 20μm (TIFF 10078 kb)

401_2018_1824_MOESM2_ESM.tif

Representative Examples of Semiquantitative Scoring for FBG Extravasation in Human Tissue. Representative examples (a) Minimal (score 1), (b) Moderate (score 2) and (c) Extensive (score 3) FBG extravasation in human postmortem material including the entire hemi-coronal section of the parasagittal cortex at the level of the mid-thalamus to include the cingulate gyrus and corpus callosum. Scale bars (a-c) 1mm (TIFF 2023 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Johnson, V.E., Weber, M.T., Xiao, R. et al. Mechanical disruption of the blood–brain barrier following experimental concussion. Acta Neuropathol 135, 711–726 (2018). https://doi.org/10.1007/s00401-018-1824-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-018-1824-0

Keywords

  • Mild traumatic brain injury
  • Concussion
  • Blood–brain barrier
  • Fibrinogen
  • Gliosis
  • Biomechanics