Repetitive Concussive and Subconcussive Injury in a Human Tau Mouse Model Results in Chronic Cognitive Dysfunction and Disruption of White Matter Tracts, But Not Tau Pathology

Gangolli, Mihika; Benetatos, Joseph; Esparza, Thomas J.; E, Fountain; Seneviratne, Shamilka; Brody, David L.

doi:10.1089/neu.2018.5700

Cited by 22 publications

(22 citation statements)

References 58 publications

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“…[5][6][7][8] Also, data from military and sports-related TBI suggest that this risk is increased when multiple mTBIs are sustained. [9][10][11][12][13][14] Thus, biomarkers that can objectively measure severity of brain injury and predict prognosis of patients with TBI have become an important research focus.…”

Section: Introductionmentioning

confidence: 99%

Neurofilament light as a biomarker in traumatic brain injury

et al. 2020

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Objective:To determine if serum neurofilament light (NfL) correlates with cerebrospinal fluid (CSF) NfL, TBI diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) estimates of traumatic axonal injury (TAI).Methods:Participants were prospectively enrolled in Sweden and the United States between 2011-2019. The Swedish cohort included 45 hockey players with acute concussion (AC) sampled at six days, 31 repetitive concussion (RC) with persistent post-concussive symptoms (PCS) assessed with paired CSF and serum (median, 1.3 years after concussion), 28 preseason controls, and 14 non-athletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls. Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n=30), 90 (n=48), and 180 (n=59) days, and 1 (n=84), 2 (n=57), 3 (n=46), 4 (n=38), and 5 (n=29) years after injury.Results:In athletes with paired specimens, CSF and serum NfL were correlated (r=0.71, p<0.0001). CSF and serum NfL distinguished players with PCS >1-year from PCS ≤1-year (Area Under the Receiver-Operating Characteristic Curve [AUROC], 0.81 and 0.80). The AUROC for PCS >1-year vs preseason controls were 0.97. In the clinic-based cohort, NfL at enrolment distinguished patients with mild vs moderate vs severe TBI (p<0.001 and p=0.048). Serum NfL decreased over the course of five years (ß=–0.09 log pg/mL, p<0.0001), but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI.Conclusions:Serum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI.Classification of Evidence:This study provides Class III evidence that increased concentrations of NfL distinguish TBI from controls.

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Section: Introductionmentioning

confidence: 99%

Neurofilament light as a biomarker in traumatic brain injury

et al. 2020

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“…These studies sought to explore the TBI-CTE link with adult 4–18 months old mice [ 18 , 23 , 24 ], using diffuse closed head injury and focal contusion models of TBI [ 18 , 24 ]. Recent longitudinal studies using adult transgenic mice expressing human tau and rCHI models showed evidence of white matter disease and cognitive and motor dysfunction up to one-year post-injury, without showing a difference in p-tau deposition between sham and injured mice [ 25 ]. Despite the prevalence of adolescent concussions and the recently reported risk of CTE in this population, the impact of rCHI on the progression of tau pathobiology in adolescent mice has not been fully explored.…”

Section: Introductionmentioning

confidence: 99%

Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice

Izzy

Brown-Whalen

Yahya

et al. 2021

IJMS

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Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

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“…There are a small number of rCBI studies in mice that have extended observations to a year or longer following injuries and continue to report functional and neuropathological effects of rCBI (17–20). These studies, however, have been limited to male mice.…”

Section: Introductionmentioning

confidence: 99%

Chronic Neurobehavioral Sex Differences in a Murine Model of Repetitive Concussive Brain Injury

Tucker

Velosky

et al. 2019

Front. Neurol.

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Traumatic brain injury (TBI) resulting from repeated head trauma is frequently characterized by diffuse axonal injury and long-term motor, cognitive and neuropsychiatric symptoms. Given the delay, often decades, between repeated head traumas and the presentation of symptoms in TBI patients, animal models of repeated injuries should be studied longitudinally to properly assess the longer-term effects of multiple concussive injuries on functional outcomes. In this study, male and cycling female C57BL/6J mice underwent repeated (three) concussive brain injuries (rCBI) delivered via a Leica ImpactOne cortical impact device and were assessed chronically on motor (open field and rotarod), cognitive (y-maze and active place avoidance), and neuropsychiatric (marble-burying, elevated zero maze and tail suspension) tests. Motor deficits were significant on the rotarod on the day following the injuries, and slight impairment remained for up to 6 months. All mice that sustained rCBI had significant cognitive deficits on the active place avoidance test and showed greater agitation (less immobility) in the tail suspension test. Only injured male mice were significantly hyperactive in the open field, and had increased time spent in the open quadrants of the elevated zero maze. One year after the injuries, mice of both sexes exhibited persistent pathological changes by the presence of Prussian blue staining (indication of prior microbleeds), primarily in the cortex at the site of the injury, and increased GFAP staining in the perilesional cortex and axonal tracts (corpus callosum and optic tracts). These data demonstrate that a pathological phenotype with motor, cognitive, and neuropsychiatric symptoms can be observed in an animal model of rCBI for at least one year post-injury, providing a pre-clinical setting for the study of the link between multiple brain injuries and neurodegenerative disorders. Furthermore, this is the first study to include both sexes in a pre-clinical long-term rCBI model, and female mice are less impaired functionally than males.

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Repetitive Concussive and Subconcussive Injury in a Human Tau Mouse Model Results in Chronic Cognitive Dysfunction and Disruption of White Matter Tracts, But Not Tau Pathology

Cited by 22 publications

References 58 publications

Neurofilament light as a biomarker in traumatic brain injury

Neurofilament light as a biomarker in traumatic brain injury

Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice

Chronic Neurobehavioral Sex Differences in a Murine Model of Repetitive Concussive Brain Injury

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