scholarly journals Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury

2020 ◽  
Author(s):  
Jessica L. Fletcher ◽  
Larissa K. Dill ◽  
Rhiannon J. Wood ◽  
Sharon Wang ◽  
Kate Robertson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Corpus Callosum ◽  
Acute Treatment ◽  
Social Memory ◽  
Reactive Gliosis ◽  
Post Injury ◽  
External Capsule ◽  
Injured Brain ◽  
Neurobehavioral Outcomes

ABSTRACTYoung children have a high risk of sustaining a traumatic brain injury (TBI), which can have debilitating life-long consequences. Importantly, the young brain shows particular vulnerability to injury, likely attributed to ongoing maturation of the myelinating nervous system at the time of insult. Here, we examined the effect of acute treatment with partial tropomyosin receptor kinase B (TrkB) agonist, LM22A-4, on the pathological and neurobehavioral outcomes after pediatric TBI, with the hypothesis that targeting TrkB would minimize tissue damage and support functional recovery. We focused on myelinated tracts— the corpus callosum and external capsules—based on recent evidence that TrkB activation potentiates oligodendrocyte remyelination. Male mice at postnatal day 21 received an experimental TBI or sham surgery. Acutely post-injury, extensive cell death, a robust glial response and disruption of compact myelin were evident in the injured brain. TBI or sham mice then received intranasal saline vehicle or LM22A-4 for 14 days. Behavior testing was performed from 4 weeks post-injury, and brains were collected at 5 weeks for histology. TBI mice showed hyperactivity, reduced anxiety-like behavior, and social memory impairments. LM22A-4 ameliorated the abnormal anxiolytic phenotype but had no effect on social memory deficits. Use of spectral confocal reflectance microscopy detected persistent myelin fragmentation in the external capsule of TBI mice at 5 weeks post-injury, which was accompanied by regionally distinct deficits in oligodendrocyte progenitor cells and postmitotic oligodendrocytes, as well as chronic reactive gliosis and atrophy of the corpus callosum and injured external capsule. LM22A-4 treatment ameliorated myelin deficits in the perilesional external capsule, as well as tissue volume loss and the extent of reactive gliosis. However, there was no effect of this TrkB agonist on oligodendroglial populations detected at 5 weeks post-injury. Collectively, our results demonstrate that targeting TrkB immediately after TBI during early life confers neuroprotection and preserves myelin integrity, and this was associated with some improved neurobehavioral outcomes as the pediatric injured brain matures.

scholarly journals GERIATRIC TRAUMATIC BRAIN INJURY AND ALZHEIMER’S DISEASE SHARE SIMILAR PATTERNS OF WHITE MATTER DEGRADATION

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S96-S96
Author(s):  
Andrei Irimia ◽  
Kenneth Rostowsky ◽  
Nikhil Chaudhari ◽  
Maria Calvillo ◽  
Sean Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Corpus Callosum ◽  
Diffusion Tensor ◽  
Future Research ◽  
Post Injury ◽  
Significant Difference

Abstract Although mild traumatic brain injury (mTBI) and Alzheimer’s disease (AD) are associated with white matter (WM) degradation, the nature of these alterations and the outcomes of their comparison have not been elucidated. Diffusion tensor imaging (DTI) has been utilized in both conditions, and has uncovered decreases in the fractional anisotropy (FA) of the corpus callosum and cingulum bundle, compared to healthy control (HC) volunteers [1, 2]. Despite mTBI being a potential risk factor for AD, no systematic quantitative comparison has been drawn between their WM degradation patterns. Here we investigated WM FA differences using DTI and tract-based spatial statistics (TBSS) between age- and sex-matched adults: 33 chronic mTBI patients, 67 AD patients and 81 HC participants. T1-weighted magnetic resonance imaging (MRI) and DTI were acquired at 3T. mTBI patients were scanned acutely and ~6 months post-injury. FSL software was used for artefact correction, FA computation and TBSS implementation. Statistical comparison of WM FA patterns between mTBI and AD patients was achieved by two one-sided t tests (TOSTs) of statistical equivalence, with equivalence bounds defined where Cohen’s d < 0.3. A significant difference was found between the FA means of mTBI vs. HC groups, and the AD vs. HC groups (p < 0.01, corrected). Mean FA differences between mTBI and AD were statistically equivalent in the corpus callosum and in the inferior longitudinal fasciculus (p < 0.05, corrected). Future research should focus on clarifying the similarities between mTBI and AD, potentially leading to novel hypotheses and improved AD diagnosis.

Cognitive and neurobehavioral functioning after mild versus moderate traumatic brain injury in older adults

2001 ◽  
Vol 7 (3) ◽  
pp. 373-383 ◽  
Author(s):  
FELICIA C. GOLDSTEIN ◽  
HARVEY S. LEVIN ◽  
WILLIAM P. GOLDMAN ◽  
ALLISON N. CLARK ◽  
TRACY KENEHAN ALTONEN
Keyword(s):  
Older Adults ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Outcome ◽  
Cognitive Measures ◽  
Post Injury ◽  
Mild Tbi ◽  
Moderate Traumatic Brain Injury ◽  
Comparable Control ◽  
Neurobehavioral Outcomes

This study evaluated the early cognitive and neurobehavioral outcomes of older adults with mild versus moderate traumatic brain injury (TBI). Thirty-five patients who were age 50 years and older and sustained mild or moderate TBI were prospectively recruited from acute care hospitals. Patients were administered cognitive and neurobehavioral measures up to 2 months post-injury. Demographically comparable control participants received the same measures. Patients and controls did not have previous histories of substance abuse, neuropsychiatric disturbance, dementia, or neurologic illness. Moderate TBI patients performed significantly poorer than mild TBI patients and controls on most cognitive measures, whereas the mild patients performed comparably to controls. In contrast, both mild and moderate patients exhibited significantly greater depression and anxiety/somatic concern than controls. The results indicate that the classification of TBI as mild versus moderate is prognostically meaningful as applied to older adults. The findings extend previous investigations in young adults by demonstrating a relatively good cognitive outcome on objective measures, but subjective complaints after a single, uncomplicated mild TBI in older persons. (JINS, 2001, 7, 373–383.)

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.

scholarly journals Long-Term Cognitive Deficits After Traumatic Brain Injury Associated With Microglia Activation

2021 ◽  
Author(s):  
Esber Saba ◽  
Mona Karout ◽  
Leila Nasralla ◽  
Firas Kobeissy ◽  
Hala Darwish ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Learning And Memory ◽  
Cognitive Deficits ◽  
Head Injuries ◽  
Spatial Learning And Memory ◽  
Post Injury ◽  
Color Flow ◽  
Injured Brain ◽  
The Central Nervous System

Abstract Traumatic Brain Injury (TBI) is the most prevalent of all head injuries, and based on the severity of the injury, it may result in chronic neurologic and cognitive deficits. Microglia play an essential role in homeostasis and diseases of the central nervous system. We hypothesize that microglia may play a beneficial or detrimental role in TBI depending on their state of activation and duration.In the present study, we evaluated whether TBI results in a spatiotemporal change in microglia phenotype and whether it affects sensory-motor or learning and memory functions in male C57BL/6 mice. We used a panel of neurological and behavioral tests and a multi-color flow cytometry-based data analysis followed by unsupervised clustering to evaluate isolated microglia from injured brain tissue. We characterized several microglial phenotypes and their association with cognitive deficits. TBI results in a spatiotemporal increase in highly activated microglia that correlated negatively with spatial learning and memory at 35 days post-injury. These observations could define therapeutic windows and accelerate translational research to improve patient outcomes.

Traumatic Brain Injury: A Trauma Surgeon's Perspective

2012 ◽  
Vol 22 (3) ◽  
pp. 82-89
Author(s):  
Oscar D. Guillamondegui
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Multidisciplinary Approach ◽  
Trauma Team ◽  
The United States ◽  
Long Term Outcomes ◽  
Term Care ◽  
Injured Brain ◽  
The Moment

Traumatic brain injury (TBI) is a serious epidemic in the United States. It affects patients of all ages, race, and socioeconomic status (SES). The current care of these patients typically manifests after sequelae have been identified after discharge from the hospital, long after the inciting event. The purpose of this article is to introduce the concept of identification and management of the TBI patient from the moment of injury through long-term care as a multidisciplinary approach. By promoting an awareness of the issues that develop around the acutely injured brain and linking them to long-term outcomes, the trauma team can initiate care early to alter the effect on the patient, family, and community. Hopefully, by describing the care afforded at a trauma center and by a multidisciplinary team, we can bring a better understanding to the armamentarium of methods utilized to treat the difficult population of TBI patients.

scholarly journals A-126 Clinical Utility of Risk Factors to Predict Self-reported Neurobehavioral Outcome Following Traumatic Brain Injury: PTSD, Sleep, Resilience, and Lifetime Blast Exposure

2020 ◽  
Vol 35 (6) ◽  
pp. 919-919
Author(s):  
Lange R ◽  
Lippa S ◽  
Hungerford L ◽  
Bailie J ◽  
French L ◽  
...  
Keyword(s):  
Risk Factors ◽  
Traumatic Brain Injury ◽  
Risk Factor ◽  
Brain Injury ◽  
Clinical Utility ◽  
Poor Sleep ◽  
Post Injury ◽  
Poor Outcome ◽  
Blast Exposure ◽  
Neurobehavioral Outcome

Abstract Objective To examine the clinical utility of PTSD, Sleep, Resilience, and Lifetime Blast Exposure as ‘Risk Factors’ for predicting poor neurobehavioral outcome following traumatic brain injury (TBI). Methods Participants were 993 service members/veterans evaluated following an uncomplicated mild TBI (MTBI), moderate–severe TBI (ModSevTBI), or injury without TBI (Injured Controls; IC); divided into three cohorts: (1) < 12 months post-injury, n = 237 [107 MTBI, 71 ModSevTBI, 59 IC]; (2) 3-years post-injury, n = 370 [162 MTBI, 80 ModSevTBI, 128 IC]; and (3) 10-years post-injury, n = 386 [182 MTBI, 85 ModSevTBI, 119 IC]. Participants completed a 2-hour neurobehavioral test battery. Odds Ratios (OR) were calculated to determine whether the ‘Risk Factors’ could predict ‘Poor Outcome’ in each cohort separately. Sixteen Risk Factors were examined using all possible combinations of the four risk factor variables. Poor Outcome was defined as three or more low scores (< 1SD) on five TBI-QOL scales (e.g., Fatigue, Depression). Results In all cohorts, the vast majority of risk factor combinations resulted in ORs that were ‘clinically meaningful’ (ORs > 3.00; range = 3.15 to 32.63, all p’s < .001). Risk factor combinations with the highest ORs in each cohort were PTSD (Cohort 1 & 2, ORs = 17.76 and 25.31), PTSD+Sleep (Cohort 1 & 2, ORs = 18.44 and 21.18), PTSD+Sleep+Resilience (Cohort 1, 2, & 3, ORs = 13.56, 14.04, and 20.08), Resilience (Cohort 3, OR = 32.63), and PTSD+Resilience (Cohort 3, OR = 24.74). Conclusions Singularly, or in combination, PTSD, Poor Sleep, and Low Resilience were strong predictors of poor outcome following TBI of all severities and injury without TBI. These variables may be valuable risk factors for targeted early interventions following injury.

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.

Blood Biomarkers Relate to Cognitive Performance Years after Traumatic Brain Injury in Service Members and Veterans

2020 ◽  
pp. 1-7
Author(s):  
Sara M. Lippa ◽  
Jessica Gill ◽  
Tracey A. Brickell ◽  
Louis M. French ◽  
Rael T. Lange
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Outcome ◽  
Service Members ◽  
Neurocognitive Performance ◽  
Blood Biomarkers ◽  
Post Injury ◽  
Blood Draw ◽  
Neurofilament Light ◽  
History Of

Abstract Objective: This study examines the relationship of serum total tau, neurofilament light (NFL), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) with neurocognitive performance in service members and veterans with a history of traumatic brain injury (TBI). Method: Service members (n = 488) with a history of uncomplicated mild (n = 172), complicated mild, moderate, severe, or penetrating TBI (sTBI; n = 126), injured controls (n = 116), and non-injured controls (n = 74) prospectively enrolled from Military Treatment Facilities. Participants completed a blood draw and neuropsychological assessment a year or more post-injury. Six neuropsychological composite scores and presence/absence of mild neurocognitive disorder (MNCD) were evaluated. Within each group, stepwise hierarchical regression models were conducted. Results: Within the sTBI group, increased serum UCH-L1 was related to worse immediate memory and delayed memory (R2Δ = .065–.084, ps < .05) performance, while increased GFAP was related to worse perceptual reasoning (R2Δ = .030, p = .036). Unexpectedly, within injured controls, UCH-L1 and GFAP were inversely related to working memory (R2Δ = .052–.071, ps < .05), and NFL was related to executive functioning (R2Δ = .039, p = .021) and MNCD (Exp(B) = 1.119, p = .029). Conclusions: Results suggest GFAP and UCH-L1 could play a role in predicting poor cognitive outcome following complicated mild and more severe TBI. Further investigation of blood biomarkers and cognition is warranted.

scholarly journals Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Amer Toutonji ◽  
Mamatha Mandava ◽  
Silvia Guglietta ◽  
Stephen Tomlinson
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Complement System ◽  
Classical Pathway ◽  
Post Injury ◽  
Complement Inhibition ◽  
Time Points ◽  
Complement Gene ◽  
The Complement System

AbstractActivation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

scholarly journals 3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

2021 ◽  
Vol 22 (15) ◽  
pp. 8276
Author(s):  
Pen-Sen Huang ◽  
Ping-Yen Tsai ◽  
Ling-Yu Yang ◽  
Daniela Lecca ◽  
Weiming Luo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Short Term Memory ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Cognitive Behaviors ◽  
Moderate Traumatic Brain Injury ◽  
Short And Long Term ◽  
Behavioral Impairments ◽  
Hippocampal Neurodegeneration

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6′-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.

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