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dc.contributor.authorTagge, Chad A.en_US
dc.contributor.authorFisher, Andrew M.en_US
dc.contributor.authorMinaeva, Olga V.en_US
dc.contributor.authorGaudreau-Balderrama, Amandaen_US
dc.contributor.authorMoncaster, Juliet A.en_US
dc.contributor.authorZhang, Xiao-Leien_US
dc.contributor.authorWojnarowicz, Mark W.en_US
dc.contributor.authorCasey, Noelen_US
dc.contributor.authorLu, Haiyanen_US
dc.contributor.authorKokiko-Cochran, Olga N.en_US
dc.contributor.authorSaman, Sudaden_US
dc.contributor.authorEricsson, Mariaen_US
dc.contributor.authorOnos, Kristen D.en_US
dc.contributor.authorVeksler, Ronelen_US
dc.contributor.authorSenatorov, Vladimir V.en_US
dc.contributor.authorKondo, Asamien_US
dc.contributor.authorZhou, Xiao Z.en_US
dc.contributor.authorMiry, Omiden_US
dc.contributor.authorVose, Linnea R.en_US
dc.contributor.authorGopaul, Katisha R.en_US
dc.contributor.authorUpreti, Chiragen_US
dc.contributor.authorNowinski, Christopher J.en_US
dc.contributor.authorCantu, Robert C.en_US
dc.contributor.authorAlvarez, Victor E.en_US
dc.contributor.authorHildebrandt, Audrey M.en_US
dc.contributor.authorFranz, Erich S.en_US
dc.contributor.authorKonrad, Januszen_US
dc.contributor.authorHamilton, James A.en_US
dc.contributor.authorHua, Ningen_US
dc.contributor.authorTripodis, Yorghosen_US
dc.contributor.authorAnderson, Andrew T.en_US
dc.contributor.authorHowell, Gareth R.en_US
dc.contributor.authorKaufer, Danielaen_US
dc.contributor.authorHall, Garth F.en_US
dc.contributor.authorLu, Kun P.en_US
dc.contributor.authorRansohoff, Richard M.en_US
dc.contributor.authorCleveland, Robin O.en_US
dc.contributor.authorKowall, Neil Wen_US
dc.contributor.authorStein, Thor D.en_US
dc.contributor.authorLamb, Bruce T.en_US
dc.contributor.authorHuber, Bertrand R.en_US
dc.contributor.authorMoss, William C.en_US
dc.contributor.authorFriedman, Alonen_US
dc.contributor.authorStanton, Patric K.en_US
dc.contributor.authorMcKee, Ann C.en_US
dc.contributor.authorGoldstein, Lee Een_US
dc.date.accessioned2019-11-13T16:22:40Z
dc.date.available2019-11-13T16:22:40Z
dc.date.issued2018-02-01
dc.identifierhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000424217900019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=6e74115fe3da270499c3d65c9b17d654
dc.identifier.citationChad A Tagge, Andrew M Fisher, Olga V Minaeva, Amanda Gaudreau-Balderrama, Juliet A Moncaster, Xiao-Lei Zhang, Mark W Wojnarowicz, Noel Casey, Haiyan Lu, Olga N Kokiko-Cochran, Sudad Saman, Maria Ericsson, Kristen D Onos, Ronel Veksler, Vladimir V Senatorov, Asami Kondo, Xiao Z Zhou, Omid Miry, Linnea R Vose, Katisha R Gopaul, Chirag Upreti, Christopher J Nowinski, Robert C Cantu, Victor E Alvarez, Audrey M Hildebrandt, Erich S Franz, Janusz Konrad, James A Hamilton, Ning Hua, Yorghos Tripodis, Andrew T Anderson, Gareth R Howell, Daniela Kaufer, Garth F Hall, Kun P Lu, Richard M Ransohoff, Robin O Cleveland, Neil W Kowall, Thor D Stein, Bruce T Lamb, Bertrand R Huber, William C Moss, Alon Friedman, Patric K Stanton, Ann C McKee, Lee E Goldstein. 2018. "Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model." BRAIN, Volume 141, pp. 422 - 458 (37). https://doi.org/10.1093/brain/awx350
dc.identifier.issn0006-8950
dc.identifier.issn1460-2156
dc.identifier.urihttps://hdl.handle.net/2144/38497
dc.description.abstractThe mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood–brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood–brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.en_US
dc.description.sponsorshipNIH F31NS077796 (C.A.T.), NIH 5T32EB006359 (C.A.T.), NIH 1F31NS080564 (A.G.B.), University of California, Berkeley Bakar Fellowship (D.K.). NIH R01AG029385 (K.P.L.), NIH R01NS32151 (R.M.R.), NIH R01NS044421 (P.K.S.), NIH-NIA Boston University Alzheimer's Disease Center P30AG13846 and supplement 0572063345 (N.W.K.), NIH-NIA Boston University Framingham Heart Study R01AG1649, NIH-NINDS 1UO1NS086659 (A.C.M.); U.S. Department of Veterans Affairs Veterans Affairs Biorepository CSP 501 (A.C.M.), Veterans Health Administration Clinical Sciences Research and Development Merit Award I01-CX001038 (T.D.S.); U.S. Department of Defense W81XWH-13-2-0064 and VA I01 RX 002170 (A.C.M.); Peer Reviewed Alzheimer's Research Program (DoD-PRARP) 13267017 (A.C.M.), DoD-PRARP W81XWH1310263 (L.E.G.); U.S. Department of Energy contract to Lawrence Livermore National Laboratory DE-AC52-07NA27344 (A.T.A., W.C.M.). Alzheimer's Association NIRG-305779 (T.D.S.), European Union Seventh Framework Program EPITARGET 602102 (A.F.), Israel Science Foundation (A.F.), Canadian Institute of Health Research (A.F.), National Operating Committee on Standards for Athletic Equipment (A.C.M.), The Linden Fund (P.K.S.) Concussion Legacy Foundation (A.C.M., L.E.G.), WAVE (A.C.M., L.E.G.); unrestricted gifts from the Andlinger Foundation (A.C.M.), WAVE (A.C.M.), National Football League (A.C.M.); Crown Family for support of the US-Israel TBI Collaborative Research Program (A.F., L.E.G.). (F31NS077796 - NIH; 5T32EB006359 - NIH; 1F31NS080564 - NIH; R01AG029385 - NIH; R01NS32151 - NIH; R01NS044421 - NIH; University of California, Berkeley Bakar Fellowship; P30AG13846 - NIH-NIA Boston University Alzheimer's Disease Center; 0572063345 - NIH-NIA Boston University Alzheimer's Disease Center; R01AG1649 - NIH-NIA Boston University Framingham Heart Study; 1UO1NS086659 - NIH-NINDS; CSP 501 - U.S. Department of Veterans Affairs Veterans Affairs Biorepository; I01-CX001038 - Veterans Health Administration Clinical Sciences Research and Development Merit Award; W81XWH-13-2-0064 - U.S. Department of Defense; VA I01 RX 002170 - U.S. Department of Defense; 13267017 - Peer Reviewed Alzheimer's Research Program (DoD-PRARP); W81XWH1310263 - DoD-PRARP; DE-AC52-07NA27344 - U.S. Department of Energy; NIRG-305779 - Alzheimer's Association; 602102 - European Union Seventh Framework Program EPITARGET; Israel Science Foundation; Canadian Institute of Health Research; National Operating Committee on Standards for Athletic Equipment; Linden Fund; Concussion Legacy Foundation; WAVE; National Football League; Crown Family)en_US
dc.format.extent422 - 458 (37)en_US
dc.languageEnglish
dc.publisherOXFORD UNIV PRESSen_US
dc.relation.ispartofBrain
dc.rights© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.coen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectLife sciences & biomedicineen_US
dc.subjectClinical neurologyen_US
dc.subjectNeurosciencesen_US
dc.subjectNeurosciences & neurologyen_US
dc.subjectConcussionen_US
dc.subjectTraumatic brain injuryen_US
dc.subjectChronic traumatic encephalopathyen_US
dc.subjectTau proteinen_US
dc.subjectTREM2en_US
dc.subjectAction potentialsen_US
dc.subjectAdolescenten_US
dc.subjectAnimalsen_US
dc.subjectAthletesen_US
dc.subjectAthletic injuriesen_US
dc.subjectBrainen_US
dc.subjectBrain concussionen_US
dc.subjectCohort studiesen_US
dc.subjectComputer simulationen_US
dc.subjectCraniocerebral traumaen_US
dc.subjectDNA-binding proteinsen_US
dc.subjectDisease models, animalen_US
dc.subjectFemaleen_US
dc.subjectGene expression regulationen_US
dc.subjectHippocampusen_US
dc.subjectHumansen_US
dc.subjectMaleen_US
dc.subjectMiceen_US
dc.subjectMice, inbred C57BLen_US
dc.subjectModels, neurologicalen_US
dc.subjectPrefrontal cortexen_US
dc.subjectReceptors, CCR2en_US
dc.subjectReceptors, Interleukin-8Aen_US
dc.subjectTauopathiesen_US
dc.subjectVascular system injuriesen_US
dc.subjectYoung adulten_US
dc.subjectMedical and health sciencesen_US
dc.subjectPsychology and cognitive sciencesen_US
dc.subjectNeurology & neurosurgeryen_US
dc.titleConcussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse modelen_US
dc.typeArticleen_US
dc.description.versionPublished versionen_US
dc.identifier.doi10.1093/brain/awx350
pubs.elements-sourceweb-of-scienceen_US
pubs.notesEmbargo: Not knownen_US
pubs.organisational-groupBoston Universityen_US
pubs.organisational-groupBoston University, College of Engineeringen_US
pubs.organisational-groupBoston University, College of Engineering, Department of Electrical & Computer Engineeringen_US
pubs.organisational-groupBoston University, School of Medicineen_US
pubs.organisational-groupBoston University, School of Public Healthen_US
pubs.publication-statusPublisheden_US
dc.identifier.mycv317829


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© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.co
Except where otherwise noted, this item's license is described as © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.co