Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model

Tagge, Chad A.; Fisher, Andrew M.; Minaeva, Olga; Gaudreau-Balderrama, Amanda; Moncaster, Juliet A.; Zhang, Xiao Lei; Wojnarowicz, Mark; Casey, Noel; Lu, Haiyan; Kokiko-Cochran, Olga N.; Saman, Sudad; Ericsson, Maria; Onos, Kristen D.; Veksler, Ronel; Senatorov, Vladimir V.; Kondo, Asami; Zhou, Xiao Zhen; Miry, Omid; Vose, Linnea R.; Gopaul, Katisha R.; Upreti, Chirag; Nowinski, Christopher J.; Cantu, Robert C.; Alvarez, Victor E.; Hildebrandt, Audrey M.; Franz, Erich S.; Konrad, Janusz; Hamilton, James A.; Hua, Ning; Tripodis, Yorghos; Anderson, Andrew T.; Howell, Gareth R.; Kaufer, Daniela; Hall, Garth F.; Lu, Kun Ping; Ransohoff, Richard M.; Cleveland, Robin O.; Kowall, Neil W.; Stein, Thor D.; Lamb, Bruce T.; Huber, Bertrand R.; Moss, William C.; Friedman, Alon; Stanton, Patric K.; McKee, Ann C.; Goldstein, Lee E.

doi:10.1093/brain/awx350

Cited by 324 publications

(341 citation statements)

References 206 publications

(340 reference statements)

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“…4A, B), or extravasation of exogenous tracer cadaverine [33] (Sup Fig. 4C, D), suggesting BBB is compromised after mTBI, which is consistent with findings in human patients and different animal models [43].…”

Section: Microvascular Injury In a Mouse Model Of Mtbisupporting

confidence: 88%

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Zeng

Pluimer

et al. 2020

Preprint

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Introduction: Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored. Methods:We established a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, and examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also determined the brain clearance of βamyloid, as well as amyloid pathology and cognitive functions after mTBI in the 5xFAD mouse model of AD.Results: mTBI induced microvascular injury with BBB breakdown, pericyte loss and cerebral blood flow reduction in mice, which preceded gliosis. mTBI also impaired brain amyloid clearance via the vascular pathways. More importantly, mTBI accelerated amyloid pathology and cognitive impairment in the 5xFAD mice.Discussion: Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD. Ethics approval and consent to participateThe animal experiments were approved by the Institutional Animal Care and Use Committee at the University of Southern California per NIH guidelines. BackgroundAlzheimer's disease (AD) is an age-related progressive neurodegenerative condition, manifesting amyloid plaque and neurofibrillary tangle formation, neurovascular and neuroimmune dysfunctions, and cognitive impairment [1,2]. While advanced aging increases the likelihood of AD, genetic inheritance and environmental risk factors also contribute significantly [3]. For example, Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for AD [4]. TBI is a leading cause of death and disability, particularly in young adults, resulting in a great impact on productivity and dependence on health care in later life [5,6]. Both clinical and preclinical studies have demonstrated that TBI triggers multiple neurodegenerative cascades, including axonal and dendritic damage, excitatory toxicity, neuroinflammation and cell death [7,8], as well as cerebrovascular impairment such as edema, circulatory insufficiency, and blood-brain barrier (BBB) breakdown [9,10], exhibiting a high similarity with AD [6,11]. TBI is highly prevalent during military service and contact sports, and doubles the risk of developing AD and dementia [12,13]. More importantly, it also exacerbates certain pathological events that are specific to AD, including the brain's overproduction and accumulation of β-amyloid (Aβ), and neurofibrillary tangles consisting of hyperphosphorylated Tau [14]. Yet the underlying mechanisms remain elusive.Histological and neuroimaging assessments have demonstrated that microvascular injury with...

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Section: Microvascular Injury In a Mouse Model Of Mtbisupporting

confidence: 88%

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Zeng

Pluimer

et al. 2020

Preprint

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“…Ornithine decarboxylase (ODC) could convert ornithine to putrescine and induce polyamine biosynthesis at limiting rates in several central nervous system (CNS) injuries (Longo et al, 1993;van Steeg et al, 1989). ARG1 was reported to regulate neurodegenerative disorders in immunity for the central nervous system in chronic TBI compared with a sham group (Andreasson et al, 2016;Sonia, David, & Mark, 2017;Tagge et al, 2018). GAD1 was associated with an increase in posttraumatic seizure (PTS) risk due to excitotoxicity associated with gamma-amino butyric acid (GABA) transmission after acute TBI (Darrah et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Metabolomics analysis of the hippocampus in a rat model of traumatic brain injury during the acute phase

et al. 2020

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Background: Traumatic brain injury (TBI) has increased in rank among traumatic injuries worldwide. Traumatic brain injury is a serious obstacle given that its complex pathology represents a long-term process. Recently, systems biology strategies such as metabolomics to investigate the multifactorial nature of TBI have facilitated attempts to find biomarkers and probe molecular pathways for its diagnosis and therapy. Methods:This study included a group of 20 rats with controlled cortical impact and a group of 20 sham rats. We utilized mNSS tests to investigate neurological metabolic impairments on day 1 and day 3. Furthermore, we applied metabolomics and bioinformatics to determine the metabolic perturbation caused by TBI during the acute period in the hippocampus tissue of controlled cortical impact (CCI) rats. Notably, TBI-protein-metabolite subnetworks identified from a database were assessed for associations between metabolites and TBI by the dysregulation of related enzymes and transporters. Results:Our results identified 7 and 8 biomarkers on day 1 and day 3, respectively.Additionally, related pathway disorders showed effects on arginine and proline metabolism as well as taurine and hypotaurine metabolism on day 3 in acute TBI.Furthermore, according to metabolite-protein database searches, 25 metaboliteprotein pairs were established as causally associated with TBI. Further, bioinformation indicated that these TBI-associated proteins mainly take part in 5′-nucleotidase activity and carboxylic acid transmembrane transport. In addition, interweaved networks were constructed to show that the development of TBI might be affected by metabolite-related proteins and their protein pathways. Conclusion:The overall results show that acute TBI is susceptible to metabolic disorders, and the joint metabolite-protein network analysis provides a favorable prediction of TBI pathogenesis mechanisms in the brain. The signatures in the hippocampus might be promising for the development of biomarkers and pathways relevant to acute TBI and could further guide testable predictions of the underlying mechanism of TBI.

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“…1–4 In a convenience sample of 202 deceased tackle football players, CTE was neuropathologically diagnosed in 177 participants. 5 CTE is pathologically characterized by an abnormal perivascular deposition of hyperphosphorylated tau (p-tau) in neurons and astrocytes at the depths of the cerebral sulci.…”

Section: Introductionmentioning

confidence: 99%

Age of first exposure to tackle football and chronic traumatic encephalopathy

Alosco

Mez

Tripodis

et al. 2018

Annals of Neurology

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118

136

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In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886-901.

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Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model

Cited by 324 publications

References 206 publications

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Metabolomics analysis of the hippocampus in a rat model of traumatic brain injury during the acute phase

Age of first exposure to tackle football and chronic traumatic encephalopathy

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