scholarly journals Differential Expression Patterns of TDP-43 in Single Moderate versus Repetitive Mild Traumatic Brain Injury in Mice

2021 ◽  
Vol 22 (22) ◽  
pp. 12211
Author(s):  
Tamara Janković ◽  
Petra Dolenec ◽  
Jelena Rajič Bumber ◽  
Nika Gržeta ◽  
Jasna Kriz ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Expression Patterns ◽  
Brain Trauma ◽  
Post Injury ◽  
Postsynaptic Protein ◽  
Fluid Percussion Injury ◽  
Post Traumatic ◽  
Nuclear Levels ◽  
The Brain

Traumatic brain injury (TBI) is a disabling disorder and a major cause of death and disability in the world. Both single and repetitive traumas affect the brain acutely but can also lead to chronic neurodegenerative changes. Clinical studies have shown some dissimilarities in transactive response DNA binding protein 43 (TDP-43) expression patterns following single versus repetitive TBI. We explored the acute cortical post-traumatic changes of TDP-43 using the lateral fluid percussion injury (LFPI) model of single moderate TBI in adult male mice and investigated the association of TDP-43 with post-traumatic neuroinflammation and synaptic plasticity. In the ipsilateral cortices of animals following LFPI, we found changes in the cytoplasmic and nuclear levels of TDP-43 and the decreased expression of postsynaptic protein 95 within the first 3 d post-injury. Subacute pathological changes of TDP-43 in the hippocampi of animals following LFPI and in mice exposed to repetitive mild TBI (rmTBI) were studied. Changes in the hippocampal TDP-43 expression patterns at 14 d following different brain trauma procedures showed pathological alterations only after single moderate, but not following rmTBI. Hippocampal LFPI-induced TDP-43 pathology was not accompanied by the microglial reaction, contrary to the findings after rmTBI, suggesting that different types of brain trauma may cause diverse pathophysiological changes in the brain, specifically related to the TDP-43 protein as well as to the microglial reaction. Taken together, our findings may contribute to a better understanding of the pathophysiological events following brain trauma.

scholarly journals Dynamics of clusterin protein expression in the brain and plasma following experimental traumatic brain injury

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shalini Das Gupta ◽  
Anssi Lipponen ◽  
Kaisa M. A. Paldanius ◽  
Noora Puhakka ◽  
Asla Pitkänen
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Protein Expression ◽  
Fold Increase ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Post Injury ◽  
Fluid Percussion Injury ◽  
Clusterin Protein ◽  
The Brain

AbstractProgress in the preclinical and clinical development of neuroprotective and antiepileptogenic treatments for traumatic brain injury (TBI) necessitates the discovery of prognostic biomarkers for post-injury outcome. Our previous mRNA-seq data revealed a 1.8–2.5 fold increase in clusterin mRNA expression in lesioned brain areas in rats with lateral fluid-percussion injury (FPI)-induced TBI. On this basis, we hypothesized that TBI leads to increases in the brain levels of clusterin protein, and consequently, increased plasma clusterin levels. For evaluation, we induced TBI in adult male Sprague-Dawley rats (n = 80) by lateral FPI. We validated our mRNA-seq findings with RT-qPCR, confirming increased clusterin mRNA levels in the perilesional cortex (FC 3.3, p < 0.01) and ipsilateral thalamus (FC 2.4, p < 0.05) at 3 months post-TBI. Immunohistochemistry revealed a marked increase in extracellular clusterin protein expression in the perilesional cortex and ipsilateral hippocampus (7d to 1 month post-TBI), and ipsilateral thalamus (14d to 12 months post-TBI). In the thalamus, punctate immunoreactivity was most intense around activated microglia and mitochondria. Enzyme-linked immunoassays indicated that an acute 15% reduction, rather than an increase in plasma clusterin levels differentiated animals with TBI from sham-operated controls (AUC 0.851, p < 0.05). Our findings suggest that plasma clusterin is a candidate biomarker for acute TBI diagnosis.

scholarly journals A Multiscale Model of Traumatic Brain Injury Suggests Possible Mechanisms of Post-Traumatic Psychosis

2021 ◽  
Author(s):  
Dalton A R Sakthivadivel
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Traumatic Injury ◽  
Multiscale Model ◽  
Cortical Activation ◽  
Post Injury ◽  
Regulation Of Activity ◽  
Post Traumatic ◽  
And Function ◽  
The Brain

AbstractTraumatic brain injury is a devastating injury to the brain that can have permanent or fatal effects, leading to life-long deficits or death. Among these effects is psychosis and schizophrenia, sometimes reported in the population of TBI sufferers. Here we evaluate a possible mechanism of post-traumatic psychosis, shedding light on the anomalous nature of psychosis as over-activity and brain injury as destruction. Using a multiscale model of the brain to relate molecular pathology to connectomic and macroscopic features of the brain, we identify cell lysis and membrane deformation as a possible mechanism for psychosis after injury. We also evaluate the reorganisation of functional networks and cortical activation post-injury, and find the features of a simulated brain under traumatic injury correlate with recorded results on the schizophrenic functional connectome. This provides a possible mechanism for post-traumatic psychosis, as well as a proof-of-principle of advanced multiscale modelling methods in computational psychiatry and neuromedicine. It also elaborates on the relationship between structure and function in the brain, information processing, and the delicate regulation of activity in healthy brains.

scholarly journals The Challenge of Managing Patients Suffering from TBI: The Utility of Multiparametric MRI

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 178-179
Author(s):  
John L. Sherman ◽  
Laurence J. Adams ◽  
Christen F. Kutz ◽  
Deborah York ◽  
Mitchell S. Szymczak
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Family History ◽  
Diffusion Tensor ◽  
Multiparametric Mri ◽  
Psychiatric History ◽  
Post Injury ◽  
Negative Family History ◽  
Imaging Result ◽  
The Brain

AbstractTraumatic brain injury (TBI) is a complex phenomenon affecting multiple areas of the brain in multiple ways. Both right and left hemispheres are affected as well as supratentorial and infratentorial compartments. These multifocal injuries are caused by many factors including acute mechanical injury, focal intracranial hemorrhage, blunt and rotational forces, epidural and subdural hematoma, hypoxemia, hypotension, edema, axonal damage, neuronal death, gliosis and blood brain barrier disruption. Clinicians and patients benefit by precise information about the neuroanatomical areas that are affected macroscopically, microscopically and biochemically in an individual patient.Standard imaging studies are frequently negative or grossly underestimate the severity of TBI and may exacerbate and prolong patient suffering with an imaging result of “no significant abnormality”. Specifically, sophisticated imaging tools have been developed which reveal significant damage to the brain structure including atrophy, MRI spectroscopy showing variations in neuronal metabolite N-acetyl-aspartate, elevations of membrane related Choline, and the glial metabolite myo-inositol is often observed to be increased post injury. In addition, susceptibility weighted imaging (SWI) has been shown to be more reliable for detecting microbleeds versus calcifications.We have selected two TBI patients with diffuse traumatic brain injury.The first patient is a 43-year-old male who suffered severe traumatic brain injury from a motorcycle accident in 2016. Following the accident, the patient was diagnosed with seizures, major depression, and intermittent explosive disorder. He has attempted suicide and has neurobehavioral disinhibition including severe anger, agitation and irritability. He denies psychiatric history prior to TBI and has negative family history. Following the TBI, he became physically aggressive and assaultive in public with minimal provocation. He denies symptoms of thought disorder and mania. He is negative for symptoms of  cognitive decline or encephalopathy.The second patient is a 49-year-old male who suffered at least 3 concussive blasts in the Army and a parachute injury. Following the last accident, the patient was diagnosed with major depressive disorder, panic disorder, PTSD and generalized anxiety disorder. He denies any psychiatric history prior to TBI including negative family history of psychiatric illness. In addition, he now suffers from nervousness, irritability, anger, emotional lability and concurrent concentration issues, problems completing tasks and alterations in memory.Both patients underwent 1.5T multiparametric MRI using standard T2, FLAIR, DWI and T1 sequences, and specialized sequences including susceptibility weighted (SWAN/SWI), 3D FLAIR, single voxel MRI spectroscopy (MRS), diffusion tensor imaging (DTI), arterial spin labeling perfusion (ASL) and volumetric MRI (NeuroQuant). Importantly, this exam can be performed in 30–45 minutes and requires no injections other than gadolinium in some patients. We will discuss the insights derived from the MRI which detail the injured areas, validate the severity of the brain damage, and provide insight into the psychological, motivational and physical disabilities that afflict these patients. It is our expectation that this kind of imaging study will grow in value as we link specific patterns of injury to specific symptoms and syndromes resulting in more targeted therapies in the future.

The Adam Williams Initiative: Collaborating With Community Resources to Improve Care for Traumatic Brain Injury

2014 ◽  
Vol 34 (6) ◽  
pp. 39-47 ◽  
Author(s):  
Mary Kay Bader ◽  
Sonja E. Stutzman ◽  
Sylvain Palmer ◽  
Chiedozie I. Nwagwu ◽  
Gary Goodman ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Treatment Guidelines ◽  
The United States ◽  
Brain Trauma ◽  
Successful Implementation ◽  
Team Members ◽  
Staff Members ◽  
Brain Trauma Foundation ◽  
The Brain

Background The Brain Trauma Foundation has developed treatment guidelines for the care of patients with acute traumatic brain injury. However, a method to provide broad acceptance and application of these guidelines has not been published. Objective To describe methods for the development, funding, and continued educational efforts of the Adam Williams Initiative; the experiences from the first 10 years may serve as a template for hospitals and nurses that seek to engage in long-term quality improvement collaborations with foundations and/or industry. Methods In 2004, the nonprofit Adam Williams Initiative was established with the goal of providing education and resources that would encourage hospitals across the United States to incorporate the Brain Trauma Foundation’s guidelines into practice. Results Between 2004 and 2014, 37 hospitals have been funded by the Adam Williams Initiative and have had staff members participate in an immersion experience at Mission Hospital (Mission Viejo, California) during which team members received both didactic and hands-on education in the care of traumatic brain injury. Conclusions Carefully cultivated relationships and relentless teamwork have contributed to successful implementation of the Brain Trauma Foundation’s guidelines in US hospitals.

scholarly journals A pilot study exploring pupil response measurement in mild traumatic brain injury

2015 ◽  
Vol 42 (S1) ◽  
pp. S40-S40
Author(s):  
W Ting ◽  
J Topolovec-Vranic ◽  
M McGowan ◽  
MD Cusimano
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Healthy Controls ◽  
Response Dynamics ◽  
Post Injury ◽  
Response Measurement ◽  
Pupil Response ◽  
Post Traumatic ◽  
Traumatic Symptoms

Background: Pupillometry, the measurement of pupil response dynamics via the pupillary light reflex, is seldom used in the assessment of mild traumatic brain injury (mTBI). We hypothesized that there would be quantifiable differences in detailed pupil response measurements in patients with acute and chronic mTBI. Methods: We conducted 49 bilateral pupillometry measurements, in acute mTBI patients at 1-week (N=11), 2-4w (N=9), and 3-7mo post-injury (N=3); 14 patients with persistent post-traumatic symptoms (PTS) once, and healthy controls across a first visit (N=7) and second visit 2-4w later (N=5). Results: The percentage of left pupil diameter change was significantly greater in the acute mTBI group at second visit (mean=36.3% (2.96)), compared to controls at second visit (mean=31.6% (4.39)) (F=5.87, p=0.0321). We did not identify significant differences between acute mTBI patients and controls at first visit, PTS patients versus controls, and within the acute mTBI group across three longitudinal visits. Conclusion: While these preliminary data suggest that pupillometry under these conditions does not distinguish between patients who had a recent mTBI or those with PTS and healthy controls, further research is warranted investigating pupil behavior and its clinical utility in mTBI.

scholarly journals Immunological context of brain injury

2021 ◽  
Vol 23 (1) ◽  
pp. 163-168
Author(s):  
N. G. Plekhova ◽  
I. V. Radkov ◽  
S. V. Zinoviev ◽  
V. B. Shumatov
Keyword(s):  
Traumatic Brain Injury ◽  
T Cells ◽  
Brain Injury ◽  
Positive Reaction ◽  
Mild Traumatic Brain Injury ◽  
Brain Parenchyma ◽  
Post Injury ◽  
Blood Leukocytes ◽  
Subsequent Decrease ◽  
The Brain

The parameters of several populations of immune cells (T cell populations, macrophage subpopulations) in peripheral blood and brain were studied in a clinically significant model of mild traumatic brain injury among rats. The population of resident cells of innate immunity of microglia and brain astrocytes with local tissue damage is involved in the implementation of the inflammatory response, it is also shown that in case of trauma, blood leukocytes can overcome the blood-brain barrier and penetrate the brain parenchyma. The methods of flow cytometry and immunofluorescence were used. An increase in the number of monocytes and neutrophils up to 1 day, after a mild traumatic brain injury (TBI) with a subsequent decrease to the end of the observation period was noticed. It was determined, that the number of CD45+ cells, CD3+T cells decreased at 1 days post-injury (dpi), and rose slightly by 14 dpi, the percentage of CD4+T cells continuously declined from 7 to 14 dpi, while the percentage of CD8+T cells increased from 7 to 14 dpi. With mild traumatic brain injury in animals, a significant (3-10 times) decrease in the number of microvessels with a positive reaction to the presence of SMI 71 on the 8th and 14th day after head injury was observed. Intensive staining of SMI 71 microvessels was sometimes observed with an increase in the area of a positive reaction. Thin positive deposits of the reaction product are observed in the brain of healthy animals around the wall of the microvessel. In the damaged brain, CD45high/CD11b+ positive macrophages of the M1 subpopulation appeared in the brain tissue on the 2nd day after TBI and a significant amount was observed on the 8-14th day. In the corpus callosum and ipsilateral region of the striatum, the content of cells expressing CD16/11b+ reached a maximum 8 days after TBI, which correlated with a decrease in the positive response to the presence of endothelial antigen SMI 71. Thus, in the acute period of mild TBI, the presence of neuroimmunopathological processes is determined in the brain, which can subsequently result to the dysregulation of neuroimmune connections.

scholarly journals Temporal Profile of Transporter mRNA Expression in the Brain after Traumatic Brain Injury in Developing Rats

2019 ◽  
Author(s):  
Solomon M. Adams ◽  
Fanuel T. Hagos ◽  
Jeffrey P. Cheng ◽  
Robert S. B. Clark ◽  
Patrick M. Kochanek ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mrna Expression ◽  
Neurovascular Unit ◽  
Post Injury ◽  
Adult Rats ◽  
Order Of Magnitude ◽  
Liver And Kidney ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTTraumatic brain injury (TBI) is a leading cause of death in children and young adults; however, new pharmacologic approaches have failed to improve outcomes in clinical trials. Transporter proteins are central to the maintenance of homeostasis within the neurovascular unit, and regulate drug penetration into the brain. Our objective was to measure transporter temporal changes in expression in the hippocampus and cortex after experimental TBI in developing rats. We also evaluated the expression of transporters in brain, liver, and kidney across the age spectrum in both pediatric and adult rats. Eighty post-natal day (PND)-17 rats and four adult rats were randomized to receive controlled cortical impact (CCI), sham surgery, or no surgery. mRNA transcript counts for 27 ATP-binding cassette and solute carrier transporters were measured in the hippocampus, cortex, choroid plexus, liver, and kidney at 3h, 12h, 24h, 72h, 7d, and 14d post injury. After TBI, the expression of many transporters (Abcc2, Slc15a2, Slco1a2) decreased significantly in the first 24 hours, with a return to baseline over 7-14 days. Some transporters (Abcc4, Abab1a/b, Slc22a4) showed a delayed increase in expression. Baseline expression of transporters was of a similar order of magnitude in brain tissues relative to liver and kidney. Findings suggest that transporter-regulated processes may be impaired in the brain early after TBI and are potentially involved in the recovery of the neurovascular unit. Our data also suggest that transport-dependent processes in the brain are of similar importance as those seen in organs involved in drug metabolism and excretion.Significance StatementBaseline transporter mRNA expression in the central nervous system is of similar magnitude as liver and kidney, and experimental traumatic brain injury is associated with acute decrease in expression of several transporters, while others show delayed increase or decrease in expression. Pharmacotherapy following traumatic brain injury should consider potential pharmacokinetic changes associated with transporter expression.

scholarly journals Influence of Traumatic Brain Injury on Extracellular Tau Elimination at the Blood-Brain Barrier

2021 ◽  
Author(s):  
Maxwell Eisenbaum ◽  
Andrew Pearson ◽  
Arissa Gratkowski ◽  
Benoit Mouzon ◽  
Michael Mullan ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Blood Brain Barrier ◽  
Head Trauma ◽  
Brain Barrier ◽  
Post Injury ◽  
Caveolin 1 ◽  
Mural Cells ◽  
The Brain ◽  
Angiopoietin 1

Abstract Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The current studies investigated the role of the cerebrovasculature in the elimination of extracellular tau from the brain, and the influence of r-mTBI on these processes. Following intracranial injection, the levels of exogenous tau residing in the brain were elevated in a mouse model of r-mTBI at 12 months post-injury compared to r-sham mice, indicating reduced tau elimination from the brain following head trauma. This may be the result of decreased caveolin-1 mediated tau efflux at the blood-brain barrier (BBB), as the caveolin inhibitor, methyl-β-cyclodextrin, significantly reduced tau uptake in isolated cerebrovessels and significantly decreased the basolateral-to-apical transit of tau across an in vitro model of the BBB. Moreover, we found that the upstream regulator of endothelial caveolin-1, Mfsd2a, was elevated in r-mTBI cerebrovessels compared to r-sham, which coincided with a decreased expression of cerebrovascular caveolin-1 at 6 months post-injury. Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted to a greater extent from r-mTBI cerebrovessels compared to r-sham animals. Thus, in the chronic phase post-injury, release of angiopoietin-1 from degenerating mural cells downregulates caveolin-1 expression in brain endothelia, resulting in decreased tau elimination across the BBB, which may describe the accumulation of tau species in the brain following head trauma.

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