scholarly journals Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Maxwell Eisenbaum ◽  
Andrew Pearson ◽  
Arissa Gratkowski ◽  
Benoit Mouzon ◽  
Michael Mullan ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Blood Brain Barrier ◽  
Head Trauma ◽  
Chronic Phase ◽  
Post Injury ◽  
Caveolin 1 ◽  
Mural Cells ◽  
The Brain ◽  
Angiopoietin 1

AbstractRepetitive 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 of biotin-labeled tau, the levels of exogenous labeled 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 in the chronic phase following r-mTBI (> 3 months post-injury). Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted from r-mTBI cerebrovessels to a greater extent than r-sham animals. Altogether, 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.

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.

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.

scholarly journals Electrophysiological correlates of thalamocortical function in acute severe traumatic brain injury

2021 ◽  
Author(s):  
William H. Curley ◽  
Yelena G. Bodien ◽  
David W. Zhou ◽  
Mary M. Conte ◽  
Andrea S. Foulkes ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Severe Traumatic Brain Injury ◽  
Resting State ◽  
Chronic Phase ◽  
Post Injury ◽  
Network Function ◽  
Power Spectral ◽  
Level Of Consciousness ◽  
Thalamocortical Network

Few reliable biomarkers of consciousness exist for patients with acute severe brain injury. Tools assaying the neural networks that modulate consciousness may allow for tracking of recovery. The mesocircuit model, and its instantiation as the ABCD framework, classifies resting-state EEG power spectral densities into categories reflecting widely separated levels of thalamocortical network function and correlates with outcome in post-cardiac arrest coma. We applied the ABCD framework to acute severe traumatic brain injury and tested four hypotheses: 1) EEG channel-level ABCD classifications are spatially heterogeneous and temporally variable; 2) ABCD classifications improve longitudinally, commensurate with the degree of behavioural recovery; 3) ABCD classifications correlate with behavioural level of consciousness; and 4) the Coma Recovery Scale-Revised arousal facilitation protocol improves EEG dynamics along the ABCD scale. In this longitudinal cohort study, we enrolled 20 patients with acute severe traumatic brain injury requiring intensive care and 16 healthy controls. Through visual inspection, channel-level spectra from resting-state EEG were classified based on spectral peaks within frequency bands defined by the ABCD framework: A = no peaks above delta (<4 Hz) range (complete thalamocortical disruption); B = theta (4-8 Hz) peak (severe thalamocortical disruption); C = theta and beta (13-24 Hz) peaks (moderate thalamocortical disruption); or D = alpha (8-13 Hz) and beta peaks (normal thalamocortical function). We assessed behavioural level of consciousness with the Coma Recovery Scale-Revised or neurological examination and, in 12 patients, performed repeat EEG and behavioural assessments at ≥6-months post-injury. Acutely, 95% of patients demonstrated D signals in at least one channel but exhibited heterogeneity in the proportion of different channel-level ABCD classifications (mean percent D signals: 37%, range: 0-90%). By contrast, healthy participants and patients at follow-up predominantly demonstrated signals corresponding to intact thalamocortical network function (mean percent D signals: 94%). In patients studied acutely, ABCD classifications improved after the Coma Recovery Scale-Revised arousal facilitation protocol (P<0.05), providing electrophysiological evidence for the effectiveness of this commonly performed technique. ABCD classification did not correspond with behavioural level of consciousness acutely, where patients demonstrated substantial within-session temporal variability in ABCD classifications. However, ABCD classification distinguished patients with and without command-following in the subacute-to-chronic phase of recovery (P<0.01). Patients also demonstrated significant longitudinal improvement in EEG dynamics along the ABCD scale (median change in D signals: 37%, P<0.05). These findings support the use of the ABCD framework to characterize channel-level EEG dynamics and track fluctuations in functional thalamocortical network integrity in spatial detail.

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 Executive Function Training in Chronic Traumatic Brain Injury Patients: Study Protocol

2019 ◽  
Author(s):  
Daniel Krawczyk ◽  
Kihwan Han ◽  
David Martinez ◽  
Jelena Rakic ◽  
Matthew Kmiecik ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Working Memory ◽  
Executive Function ◽  
Brain Injury ◽  
Executive Functions ◽  
Inhibitory Control ◽  
Cognitive Rehabilitation ◽  
Daily Life ◽  
Chronic Phase ◽  
Post Injury

Abstract Background: Some individuals who sustain traumatic brain injuries (TBIs) continue to experience significant cognitive impairments chronically (months-to-years post-injury). Many tests of executive function are insensitive to these executive function impairments, as such impairments may only appear during complex daily life conditions. Daily life often requires us to divide our attention and focus on abstract goals. In the current study, we compare the effects of two one-month electronic cognitive rehabilitation programs for individuals with chronic TBI. The active program (Expedition: Strategic Advantage) focuses on improving goal-directed executive functions including working memory, planning, long-term memory, and inhibitory control by challenging participants to accomplish life-like cognitive simulations. The challenge level of the simulations increase in accordance with participant achievement. The control intervention (Expedition: Informational Advantage) is identical to the active; however, the cognitive demand level is capped preventing participants from advancing beyond a set level. We will evaluate these interventions with a military veteran TBI population. Methods: One hundred individuals will be enrolled in this double-blinded clinical trial (all participants and testers are blinded to condition). Each individual will be randomly assigned to one of two interventions. The primary anticipated outcomes are improvement of daily life cognitive function skills and daily life functions. These are measured by a daily life performance task, which tests cognitive skills, and a survey that evaluates daily life functions. Secondary outcomes are also predicted to include improvements in working memory, attention, planning, and inhibitory control as measured by a neuropsychological test battery. Lastly, neuroimaging measures will be used to evaluate changes in brain networks supporting cognition pre-intervention and post-intervention. Discussion: We will test whether electronically delivered cognitive rehabilitation aimed at improving daily life functional skills will provide cognitive and daily life functional improvements for individuals in the chronic phase of TBI recovery (greater than three months post-injury). We aim to better understand the cognitive processes involved in recovery and the characteristics of individuals most likely to benefit. This study will also address the potential to observe generalizability, or transfer, from a software-based cognitive training tool toward daily life improvement. Trial Registration: ClinicalTrials.gov Identifier: NCT03704116 (retrospectively registered) https://clinicaltrials.gov/ct2/show/NCT03704116?term=tbi+krawczyk&rank=1 Keywords: Cognitive rehabilitation, traumatic brain injury, executive functions, daily life functions, memory, attention, planning. Support: Joint Warfighter Program; U. S. Dept. of Defense W81XWH-16-1-0053

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 A Role for Nanoparticles in Treating Traumatic Brain Injury

Pharmaceutics ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 473 ◽  
Author(s):  
Badrul Alam Bony ◽  
Forrest M. Kievit
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Treatment Options ◽  
Unmet Need ◽  
Economic Loss ◽  
Phase Iii ◽  
Target Engagement ◽  
Post Injury ◽  
The Brain

Traumatic brain injury (TBI) is one of the main causes of disability in children and young adults, as well as a significant concern for elderly individuals. Depending on the severity, TBI can have a long-term impact on the quality of life for survivors of all ages. The primary brain injury can result in severe disability or fatality, and secondary brain damage can increase the complexities in cellular, inflammatory, neurochemical, and metabolic changes in the brain, which can last decades post-injury. Thus, survival from a TBI is often accompanied by lifelong disabilities. Despite the significant morbidity, mortality, and economic loss, there are still no effective treatment options demonstrating an improved outcome in a large multi-center Phase III trial, which can be partially attributed to poor target engagement of delivered therapeutics. Thus, there is a significant unmet need to develop more effective delivery strategies to overcome the biological barriers that would otherwise inhibit transport of materials into the brain to prevent the secondary long-term damage associated with TBI. The complex pathology of TBI involving the blood-brain barrier (BBB) has limited the development of effective therapeutics and diagnostics. Therefore, it is of great importance to develop novel strategies to target the BBB. The leaky BBB caused by a TBI may provide opportunities for therapeutic delivery via nanoparticles (NP). The focus of this review is to provide a survey of NP-based strategies employed in preclinical models of TBI and to provide insights for improved NP based diagnostic or treatment approaches. Both passive and active delivery of various NPs for TBI are discussed. Finally, potential therapeutic targets where improved NP-mediated delivery could increase target engagement are identified with the overall goal of providing insight into open opportunities for NP researchers to begin research in TBI.

scholarly journals B-Cell Lymphoma 2 (Bcl-2) and Regulation of Apoptosis after Traumatic Brain Injury: A Clinical Perspective

Medicina ◽  
2020 ◽  
Vol 56 (6) ◽  
pp. 300
Author(s):  
Hansen Deng ◽  
John K. Yue ◽  
Benjamin E. Zusman ◽  
Enyinna L. Nwachuku ◽  
Hussam Abou-Al-Shaar ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
B Cell ◽  
Head Trauma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Post Injury ◽  
Pubmed Database

Background and Objectives: The injury burden after head trauma is exacerbated by secondary sequelae, which leads to further neuronal loss. B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein and a key modulator of the programmed cell death (PCD) pathways. The current study evaluates the clinical evidence on Bcl-2 and neurological recovery in patients after traumatic brain injury (TBI). Materials and Methods: All studies in English were queried from the National Library of Medicine PubMed database using the following search terms: (B-cell lymphoma 2/Bcl-2/Bcl2) AND (brain injury/head injury/head trauma/traumatic brain injury) AND (human/patient/subject). There were 10 investigations conducted on Bcl-2 and apoptosis in TBI patients, of which 5 analyzed the pericontutional brain tissue obtained from surgical decompression, 4 studied Bcl-2 expression as a biomarker in the cerebrospinal fluid (CSF), and 1 was a prospective randomized trial. Results: Immunohistochemistry (IHC) in 94 adults with severe TBI showed upregulation of Bcl-2 in the pericontusional tissue. Bcl-2 was detected in 36–75% of TBI patients, while it was generally absent in the non-TBI controls, with Bcl-2 expression increased 2.9- to 17-fold in TBI patients. Terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL) positivity for cell death was detected in 33–73% of TBI patients. CSF analysis in 113 TBI subjects (90 adults, 23 pediatric patients) showed upregulation of Bcl-2 that peaked on post-injury day 3 and subsequently declined after day 5. Increased Bcl-2 in the peritraumatic tissue, rising CSF Bcl-2 levels, and the variant allele of rs17759659 are associated with improved mortality and better outcomes on the Glasgow Outcome Score (GOS). Conclusions: Bcl-2 is upregulated in the pericontusional brain and CSF in the acute period after TBI. Bcl-2 has a neuroprotective role as a pro-survival protein in experimental models, and increased expression in patients can contribute to improvement in clinical outcomes. Its utility as a biomarker and therapeutic target to block neuronal apoptosis after TBI warrants further evaluation.

scholarly journals Diverse Changes in Microglia Morphology and Axonal Pathology Over One Year after Mild Traumatic Brain Injury in Pigs

2020 ◽  
Author(s):  
Michael R. Grovola ◽  
Nicholas Paleologos ◽  
Daniel P. Brown ◽  
Nathan Tran ◽  
Kathryn L. Wofford ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Mild Traumatic Brain Injury ◽  
Periventricular White Matter ◽  
Post Injury ◽  
Mild Tbi ◽  
Time Points ◽  
Axonal Pathology ◽  
The Brain

AbstractOver 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long-term neurological dysfunction. The mechanical forces that occur due to TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1 year post injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1 year post injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.

scholarly journals Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice

2019 ◽  
Author(s):  
Alexandria N. Early ◽  
Amy A. Gorman ◽  
Linda J. Van Eldik ◽  
Adam D. Bachstetter ◽  
Josh M. Morganti
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Function ◽  
Acute Injury ◽  
Post Injury ◽  
Aged Brain ◽  
Injured Brain ◽  
Acute Traumatic Brain Injury ◽  
Old Mice ◽  
The Brain

AbstractBackgroundOlder-age individuals are at the highest risk for disability from a traumatic brain injury (TBI). Astrocytes are the most numerous glia in the brain, necessary for brain function, yet there is little known about unique responses of astrocytes in the aged-brain following TBI.MethodsOur approach examined astrocytes in young adult, 4-month-old, versus aged, 18-month-old mice, at 1, 3, and 7 days post-TBI. We selected these time points to span the critical period in the transition from acute injury to presumably irreversible tissue damage and disability. Two approaches were used to define the astrocyte contribution to TBI by age interaction: 1) tissue histology and morphological phenotyping, and 2) transcriptomics on enriched astrocytes from the injured brain.ResultsAging was found to have a profound effect on the TBI-induced loss of homeostatic astrocyte function needed for maintaining water transport and edema – namely, aquaporin-4. The loss of homoeostatic responses was coupled with a progressive exacerbation of astrogliosis in the aged brain as a function of time after injury. Moreover, clasmatodendrosis, an underrecognized astrogliopathy, was found to be significantly increased in the aged brain, but not in the young brain. As a function of TBI, we observed a transitory refraction in the number of these astrocytes, which rebounded by 7 days post-injury in the aged brain. The transcriptomics found disproportionate changes in genes attributed to reactive astrocytes, inflammatory response, complement pathway, and synaptic support in aged mice following TBI compared to young mice. Additionally, our data highlight that TBI did not evoke a clear alignment with previously defined “A1/A2” dichotomy of reactive astrogliosis.ConclusionsOverall, our findings point toward a progressive phenotype of aged astrocytes following TBI that we hypothesize to be maladaptive, shedding new insights into potentially modifiable astrocyte-specific mechanisms that may underlie increased fragility of the aged brain to trauma.

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