scholarly journals New astroglial injury-defined biomarkers for neurotrauma assessment

2017 ◽  
Vol 37 (10) ◽  
pp. 3278-3299 ◽  
Author(s):  
Julia Halford ◽  
Sean Shen ◽  
Kyohei Itamura ◽  
Jaclynn Levine ◽  
Albert C Chong ◽  
...  
Keyword(s):  
Lipid Binding ◽  
Neurological Deficits ◽  
Breakdown Product ◽  
Cellular Injury ◽  
Post Injury ◽  
Mild Tbi ◽  
Delayed Cell Death ◽  
Severe Tbi ◽  
Trauma Model ◽  
Injury Progression

Traumatic brain injury (TBI) is an expanding public health epidemic with pathophysiology that is difficult to diagnose and thus treat. TBI biomarkers should assess patients across severities and reveal pathophysiology, but currently, their kinetics and specificity are unclear. No single ideal TBI biomarker exists. We identified new candidates from a TBI CSF proteome by selecting trauma-released, astrocyte-enriched proteins including aldolase C (ALDOC), its 38kD breakdown product (BDP), brain lipid binding protein (BLBP), astrocytic phosphoprotein (PEA15), glutamine synthetase (GS) and new 18-25kD-GFAP-BDPs. Their levels increased over four orders of magnitude in severe TBI CSF. First post-injury week, ALDOC levels were markedly high and stable. Short-lived BLBP and PEA15 related to injury progression. ALDOC, BLBP and PEA15 appeared hyper-acutely and were similarly robust in severe and mild TBI blood; 25kD-GFAP-BDP appeared overnight after TBI and was rarely present after mild TBI. Using a human culture trauma model, we investigated biomarker kinetics. Wounded (mechanoporated) astrocytes released ALDOC, BLBP and PEA15 acutely. Delayed cell death corresponded with GFAP release and proteolysis into small GFAP-BDPs. Associating biomarkers with cellular injury stages produced astroglial injury-defined (AID) biomarkers that facilitate TBI assessment, as neurological deficits are rooted not only in death of CNS cells, but also in their functional compromise.

scholarly journals Expansion of a fly TBI model to four levels of injury severity reveals synergistic effects of repetitive injury for moderate injury conditions

2019 ◽  
Author(s):  
Lauren J Putnam ◽  
Ashley M Willes ◽  
Brooke E Kalata ◽  
Nathaniel D Disher ◽  
Douglas J Brusich
Keyword(s):  
Injury Severity ◽  
Synergistic Effects ◽  
The United States ◽  
High Impact ◽  
Post Injury ◽  
Mild Tbi ◽  
Standard Level ◽  
Repetitive Injury ◽  
Severe Tbi ◽  
Four Levels

ABSTRACTSeveral million traumatic brain injury (TBI) events are reported in the United States annually. However, mild TBI events often go unreported, and mild and repetitive mild TBI conditions are challenging to model. Fruit flies (Drosophila melanogaster) have gained traction for the study of TBI. The best-characterized fly TBI model is the high-impact trauma (HIT) method. We replicated the HIT method and confirmed several previous findings at the standard level of injury severity. We then expanded upon the HIT model by characterizing mortality across three reduced levels of injury severity. Importantly, we found reduced mortality with reduced injury severity and synergistic effects on mortality in response to repetitive TBI by our moderate injury conditions. Last, we compared moderate, repetitive TBI to a single severe TBI via assessment of the pattern of mortality and geotaxis performance in the 24 h following TBI. We found the number and severity of injuries could result in different patterns of death, while all TBI conditions led to impaired geotaxis compared to uninjured flies at 0.5 h and 6 h post-TBI. Thus, we have extended a well-characterized model of TBI in flies, and shown the utility of this model for making unique insights into TBI across various severities, injury numbers, and time-points post-injury.

scholarly journals Serum Neurofilament Light as a Biomarker of Traumatic Brain Injury in the Presence of Concomitant Peripheral Injury

2021 ◽  
Vol 16 ◽  
pp. 117727192110534
Author(s):  
Ker Rui Wong ◽  
William T O’Brien ◽  
Mujun Sun ◽  
Glenn Yamakawa ◽  
Terence J O’Brien ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Elevated Serum ◽  
Serum Levels ◽  
Long Bone ◽  
Post Injury ◽  
Neurofilament Light ◽  
Peripheral Injury ◽  
Long Bone Fracture ◽  
Severe Tbi

Introduction: Serum neurofilament light (NfL) is an emerging biomarker of traumatic brain injury (TBI). However, the effect of peripheral injuries such as long bone fracture and skeletal muscle injury on serum NfL levels is unknown. Therefore, the aim of this study was to determine whether serum NfL levels can be used as a biomarker of TBI in the presence of concomitant peripheral injuries. Methods: Rats were randomly assigned to one of four injury groups: polytrauma (muscle crush + fracture + TBI; n = 11); peripheral injuries (muscle crush + fracture + sham-TBI; n = 12); TBI-only (sham-muscle crush + sham-fracture + TBI; n = 13); and triple-sham (n = 7). At 2-days post-injury, serum levels of NfL were quantified using a Simoa HD-X Analyzer. Results: Compared to triple-sham rats, serum NfL concentrations were higher in rats with peripheral injuries-only, TBI-only, and polytrauma. When compared to peripheral injury-only rats, serum NfL levels were higher in TBI-only and polytrauma rats. No differences were found between TBI-only and polytrauma rats. Conclusion: Serum NfL levels did not differ between TBI-only and polytrauma rats, indicating that significant peripheral injuries did not affect the sensitivity and specificity of serum NfL as a biomarker of moderate TBI. However, the finding of elevated serum NfL levels in rats with peripheral injuries in the absence of a TBI suggests that the presence of such injuries may limit the utility of NfL as a biomarker of less severe TBI (eg, concussion).

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012222
Author(s):  
Emily L Dennis ◽  
Karen Caeyenberghs ◽  
Kristen R Hoskinson ◽  
Tricia L Merkley ◽  
Stacy J Suskauer ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Behavioral Problems ◽  
Child Behavior Checklist ◽  
Injury Severity ◽  
Meta Analysis ◽  
Post Injury ◽  
Severe Tbi ◽  
Future Work

Objective:Our study addressed aims: (1) test the hypothesis that moderate-severe TBI in pediatric patients is associated with widespread white matter (WM) disruption; (2) test the hypothesis that age and sex impact WM organization after injury; and (3) examine associations between WM organization and neurobehavioral outcomes.Methods:Data from ten previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric msTBI working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline.Results:Five hundred and seven children and adolescents (244 with complicated mild to severe TBI [msTBI] and 263 controls) were included. Patients were clustered into three post-injury intervals: acute/subacute - <2 months, post-acute - 2-6 months, chronic - 6+ months. Outcomes were dMRI metrics and post-injury behavioral problems as indexed by the Child Behavior Checklist (CBCL). Our analyses revealed altered WM diffusion metrics across multiple tracts and all post-injury intervals (effect sizes ranging between d=-0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time post-injury. We observed a sex-by-group interaction: females with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (𝞫=0.043), which coincided with more parent-reported behavioral problems (𝞫=-0.0027).Conclusions:WM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically-meaningful patient subtypes.

scholarly journals Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1697-1713 ◽  
Author(s):  
Xingxing Wang ◽  
Tianna Zhou ◽  
George D Maynard ◽  
Pramod S Terse ◽  
William B Cafferty ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Recovery Of Function ◽  
Neurological Deficits ◽  
Vehicle Group ◽  
Post Injury ◽  
Nogo Receptor ◽  
Human Dose ◽  
Cord Injury ◽  
Human Primate

Abstract After CNS trauma such as spinal cord injury, the ability of surviving neural elements to sprout axons, reorganize neural networks and support recovery of function is severely restricted, contributing to chronic neurological deficits. Among limitations on neural recovery are myelin-associated inhibitors functioning as ligands for neuronal Nogo receptor 1 (NgR1). A soluble decoy (NgR1-Fc, AXER-204) blocks these ligands and provides a means to promote recovery of function in multiple preclinical rodent models of spinal cord injury. However, the safety and efficacy of this reagent in non-human primate spinal cord injury and its toxicological profile have not been described. Here, we provide evidence that chronic intrathecal and intravenous administration of NgR1-Fc to cynomolgus monkey and to rat are without evident toxicity at doses of 20 mg and greater every other day (≥2.0 mg/kg/day), and far greater than the projected human dose. Adult female African green monkeys underwent right C5/6 lateral hemisection with evidence of persistent disuse of the right forelimb during feeding and right hindlimb during locomotion. At 1 month post-injury, the animals were randomized to treatment with vehicle (n = 6) or 0.10–0.17 mg/kg/day of NgR1-Fc (n = 8) delivered via intrathecal lumbar catheter and osmotic minipump for 4 months. One animal was removed from the study because of surgical complications of the catheter, but no treatment-related adverse events were noted in either group. Animal behaviour was evaluated at 6–7 months post-injury, i.e. 1–2 months after treatment cessation. The use of the impaired forelimb during spontaneous feeding and the impaired hindlimb during locomotion were both significantly greater in the treatment group. Tissue collected at 7–12 months post-injury showed no significant differences in lesion size, fibrotic scar, gliosis or neuroinflammation between groups. Serotoninergic raphespinal fibres below the lesion showed no deficit, with equal density on the lesioned and intact side below the level of the injury in both groups. Corticospinal axons traced from biotin-dextran-amine injections in the left motor cortex were equally labelled across groups and reduced caudal to the injury. The NgR1-Fc group tissue exhibited a significant 2–3-fold increased corticospinal axon density in the cervical cord below the level of the injury relative to the vehicle group. The data show that NgR1-Fc does not have preclinical toxicological issues in healthy animals or safety concerns in spinal cord injury animals. Thus, it presents as a potential therapeutic for spinal cord injury with evidence for behavioural improvement and growth of injured pathways in non-human primate spinal cord injury.

Methodological Issues in Longitudinal Research on Cognitive Recovery after Traumatic Brain Injury: Evidence from a Systematic Review

2013 ◽  
Vol 14 (3) ◽  
pp. 450-474 ◽  
Author(s):  
Regina Schultz ◽  
Robyn L. Tate
Keyword(s):  
Systematic Review ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Longitudinal Research ◽  
Effect Sizes ◽  
Methodological Issues ◽  
Post Injury ◽  
Cognitive Recovery ◽  
Cognitive Domains ◽  
Severe Tbi

Background: Previous research addressing cognitive recovery after traumatic brain injury (TBI) in adults has predominately used cross-sectional methods. This systematic review examines longitudinal research into cognitive recovery in the first 2 years following moderate-to-severe TBI in adults and aims to identify apparent methodological issues with the existing literature.Design: Systematic review of the first 2 years post-trauma.Setting: Data were extracted from three electronic databases and manual searches of published articles until October 2012.Participants: Two hundred and forty-two participants with severe TBI and 281 comparison participants were used to calculate effect sizes.Results: Twenty papers met the selection criteria, with effect sizes computed from four studies. Moderate-to-large effect sizes were initially observed between the TBI and comparison groups on most measures (range: d = 0.2–2.8). Recovery continued in all five cognitive domains over the 2 years post-injury.Conclusions: Results demonstrated that cognitive recovery was continuous throughout the first 2 years following moderate-to-severe TBI. Findings also indicated different rates of recovery for the specific cognitive domains, highlighting the heterogeneous nature of cognitive recovery after TBI. The review highlighted several methodological issues within the limited existing literature; recommendations were developed to improve the evidence base.

scholarly journals Coping Strategies as a Predictor of Post-concussive Symptoms in Children with Mild Traumatic Brain Injury versus Mild Orthopedic Injury

2011 ◽  
Vol 17 (2) ◽  
pp. 317-326 ◽  
Author(s):  
Stacey E. Woodrome ◽  
Keith Owen Yeates ◽  
H. Gerry Taylor ◽  
Jerome Rusin ◽  
Barbara Bangert ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Coping Strategies ◽  
Mild Traumatic Brain Injury ◽  
Group Differences ◽  
Post Injury ◽  
Mild Tbi ◽  
Orthopedic Injury ◽  
Children's Coping ◽  
Over Time

AbstractThis study examined whether children's coping strategies are related to post-concussive symptoms following mild traumatic brain injury (TBI) versus orthopedic injury (OI). Participants were 8- to 15-year-old children with mild TBI (n = 167) or OI (n = 84). They rated their current preferred coping strategies and post-injury symptoms at 2 weeks (baseline) and 1, 3, and 12 months post-injury. Children's reported use of coping strategies did not vary significantly over time, so their baseline coping ratings were examined as predictors of post-concussive symptoms across time. Self-ratings of symptoms were positively related to emotion-focused strategies and negatively related to problem-focused engagement after both mild TBI and OI. Higher problem-focused disengagement predicted larger group differences in children's ratings of symptoms, suggesting that problem-focused disengagement moderates the effects of mild TBI. Coping strategies collectively accounted for approximately 10–15% of the variance in children's post-concussive symptoms over time. The findings suggest that coping may play an important role in accounting for children's perceptions of post-concussive symptoms after mild TBI. (JINS, 2011, 17, 317–326)

Evaluation of experimental spinal cord injury using cortical evoked potentials

1973 ◽  
Vol 39 (1) ◽  
pp. 75-81 ◽  
Author(s):  
Stephen H. Martin ◽  
James R. Bloedel
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cortical Response ◽  
Neurological Deficits ◽  
Cystic Degeneration ◽  
Post Injury ◽  
Content Type ◽  
Cord Injury ◽  
Cortical Responses ◽  
Control Response

✓ Experiments were performed to determine if changes in cortical evoked responses could be used to predict the extent of the neurological deficits following spinal cord injury by sudden inflation of a Fogarty balloon in the epidural space cephalad to a laminectomy. The cortical responses to stimulation of the posterior tibial nerve were recorded over the sigmoid gyrus at various times following the lesion and compared with the control response. Severe, irreversible neurological deficits occurred in cats in which the cortical response either could not be evoked immediately after injury or disappeared rapidly during this period. At the end of at least 6 weeks following injury, all of these animals were paraplegic and showed severe cystic degeneration of the spinal cord. In animals in which the post-injury cortical response did not completely disappear, only mild changes were observed in a spinal cord 6 weeks following injury. This technique may be helpful in ascertaining the severity and irreversibility of a traumatic spinal cord lesion; because the technique is simple, the method may prove helpful in the clinical management of patients with spinal cord injury.

B-57 Post-traumatic Stress Disorder is a Stronger Predictor of Long-term Neurobehavioral Outcome than Traumatic Brain Injury Severity in U.S. Military Service Members

2019 ◽  
Vol 34 (6) ◽  
pp. 1003-1003
Author(s):  
R Lange ◽  
L French ◽  
S Lippa ◽  
J Bailie ◽  
T Brickell
Keyword(s):  
Military Service ◽  
Injury Severity ◽  
Strong Predictor ◽  
Post Traumatic Stress ◽  
Mild Tbi ◽  
Severe Tbi ◽  
Post Traumatic ◽  
Main Effects ◽  
Neurobehavioral Outcome

Abstract Objective The purpose of this study was to examine long-term neurobehavioral outcome in SMVs with versus without PTSD following TBI of all severities. Methods Participants were 536 SMVs recruited into three experimental groups (TBI, injured controls [IC], non-injured controls [NIC]). Participants completed the PTSD Checklist and the TBI-Quality of Life (TBI-QOL). Participants were divided into six subgroups based on the three experimental categories, two PTSD categories (i.e., present/absent), and two broad TBI severity categories (i.e., ‘unMTBI’ [includes uncomplicated mild TBI]; and ‘smcTBI’ [includes severe TBI, moderate TBI, and complicated mild TBI): (1) NIC/PTSD-Absent, (2) IC/PTSD-Absent, (3) unMTBI/PTSD-Absent, (4) unMTBI/PTSD-Present, (5) smcTBI/PTSD-Absent, and (6) smcTBI/PTSD-Present. Results There were significant main effects across the six groups for all TBI-QOL measures (p < .001). Select pairwise comparisons revealed significantly worse scores (p < .001) on all TBI-QOL measures in all PTSD-Present groups compared to the PTSD-Absent groups (i.e., Group 3v4 and 5v6; d = 0.90 to 2.11). In contrast, when controlling for PTSD, there were no significant differences between the TBI severity groups for all TBI-QOL measures (i.e., Group 3v5 and 4v6). In the TBI sample, a series of step-wise regression analyses revealed that PTSD, but not TBI severity, was consistently a strong predictor of all TBI-QOL scales (all p’s < .001), accounting for up to 64% of the variance. Conclusions These results provide support for the very strong influence of PTSD, but not TBI severity, on long-term neurobehavioral outcome following TBI. Concurrent PTSD and TBI of all severities should be considered a risk factor for poor long-term neurobehavioral outcome that requires ongoing monitoring.

Clinical presentation of the posttraumatic stress disorder with and without traumatic brain injuries

2011 ◽  
Vol 26 (S2) ◽  
pp. 1070-1070 ◽  
Author(s):  
M.M. Simonović ◽  
M.M. Radisavljević ◽  
G.B. Grbeša
Keyword(s):  
Psychological Distress ◽  
Sleep Disturbances ◽  
Brain Injuries ◽  
Stress Disorder ◽  
Clinical Presentation ◽  
Traumatic Brain Injuries ◽  
Mild Tbi ◽  
History Of ◽  
Severe Tbi ◽  
The Difference

The aim of the investigation was to determine the difference between the severities of the symptom's in PTSD with and without the history of TBI.The estimation of the PTSD in 60 patients was performed using the CAPS-DX. The estimation of the TBI was performed using the Glasgow Coma Scale. The data were analysed using ANOVA and PostHoc analysis.Severity of the reexperiencing symptoms were higher in PTSD with TBI vs PTSD w/o TBI: in nightmares, reexperiencing, psychological distress (p < 0,05), in intrusive recollections and in total score of reexperiencing symptoms (p < 0,01). PostHoc analysis showed higher scores of intrusive recollections (p < 0,01) and psychological distress (p < 0,05) in PTSD with moderate/severe TBI vs PTSD w/o TBISeverity of the avoidance symptoms were higher in PTSD with moderate/severe TBI vs PTSD w/o TBI: in avoidance of thoughts, avoidance of activities (p < 0,05), in detachment and in total avoidance symptom's scores in PTSD with moderate/severe TBI vs PTSD w/o TBI. PostHoc analysis showed higher score of detachment in PTSD with mild TBI vs PTSD w/o TBI.Severity of hyperarousal symptoms were higher in PTSD with TBI: in sleep disturbances, difficulty concentrating (p < 0,05), and in total huperarousal symptom's score (p < 0,01). PostHoc analysis showed greater severity of sleep disturbances in PTSD with moderate/severe TBI vs PTSD with mild TBI (p < 0,05), and in PTSD without TBI (p < 0,01), and greater score of difficulties concentrating (p < 0,01) and total huperarousal symptom's (p < 0,05) in PTSD with mild TBI vs PTSD without TBI.

scholarly journals Mild TBI and risk of Parkinson disease

Neurology ◽  
2018 ◽  
Vol 90 (20) ◽  
pp. e1771-e1779 ◽  
Author(s):  
Raquel C. Gardner ◽  
Amy L. Byers ◽  
Deborah E. Barnes ◽  
Yixia Li ◽  
John Boscardin ◽  
...  
Keyword(s):  
Brain Injury ◽  
Parkinson Disease ◽  
Veterans Health Administration ◽  
Veterans Health ◽  
Health Administration ◽  
Mild Tbi ◽  
Psychiatric Comorbidities ◽  
Increased Risk ◽  
Severe Tbi

ObjectiveOur aim was to assess risk of Parkinson disease (PD) following traumatic brain injury (TBI), including specifically mild TBI (mTBI), among care recipients in the Veterans Health Administration.MethodsIn this retrospective cohort study, we identified all patients with a TBI diagnosis in Veterans Health Administration databases from October 2002 to September 2014 and age-matched 1:1 to a random sample of patients without TBI. All patients were aged 18 years and older without PD or dementia at baseline. TBI exposure and severity were determined via detailed clinical assessments or ICD-9 codes using Department of Defense and Defense and Veterans Brain Injury Center criteria. Baseline comorbidities and incident PD more than 1 year post-TBI were identified using ICD-9 codes. Risk of PD after TBI was assessed using Cox proportional hazard models adjusted for demographics and medical/psychiatric comorbidities.ResultsAmong 325,870 patients (half with TBI; average age 47.9 ± 17.4 years; average follow-up 4.6 years), 1,462 were diagnosed with PD during follow-up. Compared to no TBI, those with TBI had higher incidence of PD (no TBI 0.31%, all-severity TBI 0.58%, mTBI 0.47%, moderate-severe TBI 0.75%). In adjusted models, all-severity TBI, mTBI, and moderate-severe TBI were associated with increased risk of PD (hazard ratio [95% confidence interval]: all-severity TBI 1.71 [1.53–1.92]; mTBI 1.56 [1.35–1.80]; moderate-severe TBI 1.83 [1.61–2.07]).ConclusionsAmong military veterans, mTBI is associated with 56% increased risk of PD, even after adjusting for demographics and medical/psychiatric comorbidities. This study highlights the importance of TBI prevention, long-term follow-up of TBI-exposed veterans, and the need to determine mechanisms and modifiable risk factors for post-TBI PD.

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