scholarly journals Circulating Brain Injury Exosomal Proteins following Moderate-to-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 977 ◽  
Author(s):  
Stefania Mondello ◽  
Vivian A. Guedes ◽  
Chen Lai ◽  
Endre Czeiter ◽  
Krisztina Amrein ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Single Molecule ◽  
Tau Proteins ◽  
Clinical Implementation ◽  
Focal Lesions ◽  
Prognostic Information ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Severe Tbi

Brain injury exosomal proteins are promising blood biomarker candidates in traumatic brain injury (TBI). A better understanding of their role in the diagnosis, characterization, and management of TBI is essential for upcoming clinical implementation. In the current investigation, we aimed to explore longitudinal trajectories of brain injury exosomal proteins in blood of patients with moderate-to-severe TBI, and to evaluate the relation with the free-circulating counterpart and patient imaging and clinical parameters. Exosomal levels of glial (glial fibrillary acidic protein (GFAP)) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light chain (NFL), and total-tau (t-tau)) proteins were measured in serum of 21 patients for up 5 days after injury using single molecule array (Simoa) technology. Group-based trajectory analysis was used to generate distinct temporal exosomal biomarker profiles. We found altered profiles of serum brain injury exosomal proteins following injury. The dynamics and levels of exosomal and related free-circulating markers, although correlated, showed differences. Patients with diffuse injury displayed higher acute exosomal NFL and GFAP concentrations in serum than those with focal lesions. Exosomal UCH-L1 profile characterized by acutely elevated values and a secondary steep rise was associated with early mortality (n = 2) with a sensitivity and specificity of 100%. Serum brain injury exosomal proteins yielded important diagnostic and prognostic information and represent a novel means to unveil underlying pathophysiology in patients with moderate-to-severe TBI. Our findings support their utility as potential tools to improve patient phenotyping in clinical practice and therapeutic trials.

scholarly journals 1118 Examining the Role of Serum and Exosomal Biomarkers in Symptoms of Fatigue and Daytime Sleepiness Following Traumatic Brain Injury

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A426-A426
Author(s):  
J J Leete ◽  
C L Pattinson ◽  
V A Guedes ◽  
C Lai ◽  
C Devoto ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Single Molecule ◽  
Daytime Sleepiness ◽  
Blood Levels ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Ultrasensitive Assay ◽  
Fatigue Severity ◽  
The Relationship

Abstract Introduction Fatigue and daytime sleepiness are two of the most common chronic symptoms reported after traumatic brain injury (TBI). However, there is limited understanding of the pathophysiological mechanisms following TBI that result in these symptoms. Previous research has observed elevations in peripheral blood levels of proteins in TBI patients versus controls, including neurofilament light chain (NFL)—predominantly expressed in long myelinated subcortical axons—and glial fibrillary acidic protein (GFAP)—predominantly expressed in reactive astrocytes responding to central nervous system injuries. This study examines the relationship between serum and exosomal NFL and GFAP, and symptoms of fatigue and daytime sleepiness in TBI patients 1-year after injury. Methods Sixty-seven patients with TBIs ranging from mild to severe were included in this study. Blood samples were collected from all participants 1-year post TBI, with concentrations of GFAP and NFL measured in serum and exosomes using Single Molecule Array technology (Simoa), an ultrasensitive assay. Participants reported fatigue using the Fatigue Severity Scale (FSS), and daytime sleepiness using the Epworth Sleepiness Scale (ESS). Results A linear regression model of fatigue symptoms and exosomal NFL controlling for age revealed that fatigue was negatively associated with exosomal NFL concentrations (β = -.317, p = .041, ηp2 = -.343) and accounted for 20.2% of the change in NFL. Serum NFL concentrations were not associated with fatigue, nor were GFAP serum or exosomes. No significant associations were found between NFL, GFAP, and daytime sleepiness. Conclusion Our findings suggest that exosomal NFL may be related to mechanisms underlying TBI-related fatigue and the potential of NFL as a biomarker of fatigue. To our knowledge, this study is the first to examine the relationship between post-TBI NFL levels and fatigue symptoms. Further investigation into serum and exosome biomarkers of TBI-related fatigue and daytime sleepiness is warranted. Support National Institutes of Health and Center for Neuroscience and Regenerative Medicine

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).

scholarly journals Rapid Accumulation of Endogenous Tau Oligomers in a Rat Model of Traumatic Brain Injury

2013 ◽  
Vol 288 (23) ◽  
pp. 17042-17050 ◽  
Author(s):  
Bridget E. Hawkins ◽  
Shashirekha Krishnamurthy ◽  
Diana L. Castillo-Carranza ◽  
Urmi Sengupta ◽  
Donald S. Prough ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
The United States ◽  
Tau Proteins ◽  
Diagnostic Tools ◽  
Phosphorylated Tau ◽  
Fluid Percussion Injury ◽  
Rapid Accumulation ◽  
Severe Tbi ◽  
Effective Treatments

Traumatic brain injury (TBI) is a serious problem that affects millions of people in the United States alone. Multiple concussions or even a single moderate to severe TBI can also predispose individuals to develop a pathologically distinct form of tauopathy-related dementia at an early age. No effective treatments are currently available for TBI or TBI-related dementia; moreover, only recently has insight been gained regarding the mechanisms behind their connection. Here, we used antibodies to detect oligomeric and phosphorylated Tau proteins in a non-transgenic rodent model of parasagittal fluid percussion injury. Oligomeric and phosphorylated Tau proteins were detected 4 and 24 h and 2 weeks post-TBI in injured, but not sham control rats. These findings suggest that diagnostic tools and therapeutics that target only toxic forms of Tau may provide earlier detection and safe, more effective treatments for tauopathies associated with repetitive neurotrauma.

scholarly journals Neurofilament light chain level in traumatic brain injury

Medicine ◽  
2020 ◽  
Vol 99 (38) ◽  
pp. e22363 ◽  
Author(s):  
Wenyan Gao ◽  
Zhongshan Zhang ◽  
Xiaoling Lv ◽  
Qing Wu ◽  
Jing Yan ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Light Chain ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Chain Level

scholarly journals Blood biomarkers for mild traumatic brain injury: a selective review of unresolved issues

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Daniel B. Hier ◽  
Tayo Obafemi-Ajayi ◽  
Matthew S. Thimgan ◽  
Gayla R. Olbricht ◽  
Sima Azizi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Ct Scan ◽  
Mild Traumatic Brain Injury ◽  
Current Knowledge ◽  
Blood Biomarkers ◽  
Predictive Capacity ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Blood Biomarker

Abstract Background The use of blood biomarkers after mild traumatic brain injury (mTBI) has been widely studied. We have identified eight unresolved issues related to the use of five commonly investigated blood biomarkers: neurofilament light chain, ubiquitin carboxy-terminal hydrolase-L1, tau, S100B, and glial acidic fibrillary protein. We conducted a focused literature review of unresolved issues in three areas: mode of entry into and exit from the blood, kinetics of blood biomarkers in the blood, and predictive capacity of the blood biomarkers after mTBI. Findings Although a disruption of the blood brain barrier has been demonstrated in mild and severe traumatic brain injury, biomarkers can enter the blood through pathways that do not require a breach in this barrier. A definitive accounting for the pathways that biomarkers follow from the brain to the blood after mTBI has not been performed. Although preliminary investigations of blood biomarkers kinetics after TBI are available, our current knowledge is incomplete and definitive studies are needed. Optimal sampling times for biomarkers after mTBI have not been established. Kinetic models of blood biomarkers can be informative, but more precise estimates of kinetic parameters are needed. Confounding factors for blood biomarker levels have been identified, but corrections for these factors are not routinely made. Little evidence has emerged to date to suggest that blood biomarker levels correlate with clinical measures of mTBI severity. The significance of elevated biomarker levels thirty or more days following mTBI is uncertain. Blood biomarkers have shown a modest but not definitive ability to distinguish concussed from non-concussed subjects, to detect sub-concussive hits to the head, and to predict recovery from mTBI. Blood biomarkers have performed best at distinguishing CT scan positive from CT scan negative subjects after mTBI.

Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy

2014 ◽  
Vol 121 (3) ◽  
pp. 674-679 ◽  
Author(s):  
Kwok M. Ho ◽  
Stephen Honeybul ◽  
Cheng B. Yip ◽  
Benjamin I. Silbert
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Blood Brain Barrier ◽  
Decompressive Craniectomy ◽  
Prognostic Value ◽  
Prognostic Model ◽  
Long Term Outcomes ◽  
Prognostic Information ◽  
Severe Tbi

Object The authors assessed the risk factors and outcomes associated with blood-brain barrier (BBB) disruption in patients with severe, nonpenetrating, traumatic brain injury (TBI) requiring decompressive craniectomy. Methods At 2 major neurotrauma centers in Western Australia, a retrospective cohort study was conducted among 97 adult neurotrauma patients who required an external ventricular drain (EVD) and decompressive craniectomy during 2004–2012. Glasgow Outcome Scale scores were used to assess neurological outcomes. Logistic regression was used to identify factors associated with BBB disruption, defined by a ratio of total CSF protein concentrations to total plasma protein concentration > 0.007 in the earliest CSF specimen collected after TBI. Results Of the 252 patients who required decompressive craniectomy, 97 (39%) required an EVD to control intracranial pressure, and biochemical evidence of BBB disruption was observed in 43 (44%). Presence of disruption was associated with more severe TBI (median predicted risk for unfavorable outcome 75% vs 63%, respectively; p = 0.001) and with worse outcomes at 6, 12, and 18 months than was absence of BBB disruption (72% vs 37% unfavorable outcomes, respectively; p = 0.015). The only risk factor significantly associated with increased risk for BBB disruption was presence of nonevacuated intracerebral hematoma (> 1 cm diameter) (OR 3.03, 95% CI 1.23–7.50; p = 0.016). Although BBB disruption was associated with more severe TBI and worse long-term outcomes, when combined with the prognostic information contained in the Corticosteroid Randomization after Significant Head Injury (CRASH) prognostic model, it did not seem to add significant prognostic value (area under the receiver operating characteristic curve 0.855 vs 0.864, respectively; p = 0.453). Conclusions Biochemical evidence of BBB disruption after severe nonpenetrating TBI was common, especially among patients with large intracerebral hematomas. Disruption of the BBB was associated with more severe TBI and worse long-term outcomes, but when combined with the prognostic information contained in the CRASH prognostic model, this information did not add significant prognostic value.

scholarly journals Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Spencer Flynn ◽  
Jacqueline Leete ◽  
Pashtun Shahim ◽  
Cassandra Pattinson ◽  
Vivian A. Guedes ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Glial Fibrillary Acidic Protein ◽  
Injury Severity ◽  
Extracellular Vesicle ◽  
Individual Variability ◽  
Acidic Protein ◽  
Neurofilament Light ◽  
Ultrasensitive Assay ◽  
Severe Tbi

AbstractTraumatic brain injury (TBI) is linked to long-term symptoms in a sub-set of patients who sustain an injury, but this risk is not universal, leading us and others to question the nature of individual variability in recovery trajectories. Extracellular vesicles (EVs) are a promising, novel avenue to identify blood-based biomarkers for TBI. Here, our aim was to determine if glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) measured 1-year postinjury in EVs could distinguish patients from controls, and whether these biomarkers relate to TBI severity or recovery outcomes. EV GFAP and EV NfL were measured using an ultrasensitive assay in 72 TBI patients and 20 controls. EV GFAP concentrations were elevated in moderate and severe TBI compared to controls (p’s < 0.001) and could distinguish controls from moderate (AUC = 0.86) or severe TBI (AUC = 0.88). Increased EV GFAP and EV NfL levels were associated with lower 1-year Glasgow Outcome Scale–Extended (GOS-E) score (p’s < 0.05). These findings suggest that blood-derived EV concentrations of GFAP and NfL drawn even 1 year after injury are higher in TBI patients compared to controls, and are related to injury severity and poor recovery outcomes, suggesting that TBIs alter the activity of these biomarkers, likely contributing to individual variability in recovery.

scholarly journals Plasma glial fibrillary acidic protein and neurofilament light chain, but not tau, are biomarkers of sports-related mild traumatic brain injury

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Etienne Laverse ◽  
Tong Guo ◽  
Karl Zimmerman ◽  
Martha S Foiani ◽  
Bharat Velani ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Glial Fibrillary Acidic Protein ◽  
Mild Traumatic Brain Injury ◽  
Light Chain ◽  
Acidic Protein ◽  
Post Injury ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

Abstract Mild traumatic brain injury is a relatively common event in contact sports and there is increasing interest in the long-term neurocognitive effects. The diagnosis largely relies on symptom reporting and there is a need for objective tools to aid diagnosis and prognosis. There are recent reports that blood biomarkers could potentially help triage patients with suspected injury and normal CT findings. We have measured plasma concentrations of glial and neuronal proteins and explored their potential in the assessment of mild traumatic brain injury in contact sport. We recruited a prospective cohort of active male rugby players, who had pre-season baseline plasma sampling. From this prospective cohort, we recruited 25 players diagnosed with mild traumatic brain injury. We sampled post-match rugby players without head injuries as post-match controls. We measured plasma neurofilament light chain, tau and glial fibrillary acidic protein levels using ultrasensitive single molecule array technology. The data were analysed at the group and individual player level. Plasma glial fibrillary acidic protein concentration was significantly increased 1-h post-injury in mild traumatic brain injury cases compared to the non-injured group (P = 0.017). Pairwise comparison also showed that glial fibrillary acidic protein levels were higher in players after a head injury in comparison to their pre-season levels at both 1-h and 3- to 10-day post-injury time points (P = 0.039 and 0.040, respectively). There was also an increase in neurofilament light chain concentration in brain injury cases compared to the pre-season levels within the same individual at both time points (P = 0.023 and 0.002, respectively). Tau was elevated in both the non-injured control group and the 1-h post-injury group compared to pre-season levels (P = 0.007 and 0.015, respectively). Furthermore, receiver operating characteristic analysis showed that glial fibrillary acidic protein and neurofilament light chain can separate head injury cases from control players. The highest diagnostic power was detected when biomarkers were combined in differentiating 1-h post-match control players from 1-h post-head injury players (area under curve 0.90, 95% confidence interval 0.79–1.00, P &lt; 0.0002). The brain astrocytic marker glial fibrillary acidic protein is elevated in blood 1 h after mild traumatic brain injury and in combination with neurofilament light chain displayed the potential as a reliable biomarker for brain injury evaluation. Plasma total tau is elevated following competitive rugby with and without a head injury, perhaps related to peripheral nerve trauma and therefore total tau does not appear to be suitable as a blood biomarker.

Remote supervision of rehabilitation interventions for survivors of moderate or severe traumatic brain injury: A scoping review

2019 ◽  
Vol 26 (9) ◽  
pp. 520-535 ◽  
Author(s):  
Jennifer O’Neil ◽  
Jacquie van Ierssel ◽  
Heidi Sveistrup
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Rural Communities ◽  
Outcome Measures ◽  
Severe Traumatic Brain Injury ◽  
Scoping Review ◽  
Clinical Implementation ◽  
Intervention Delivery ◽  
Remote Supervision ◽  
Severe Tbi

Introduction Individuals with moderate or severe traumatic brain injury (TBI) often have persistent impairments upon discharge home. In rural communities, specialized rehabilitation services to address impairments can be difficult to access. The purpose of this scoping review is to examine how remote supervision is currently being used in TBI rehabilitation to identify gaps in knowledge that need to be addressed to facilitate access to and implementation of these services. Methods The main objective for this review is to identify the methods being used to deliver remote supervision for rehabilitation in a moderate or severe TBI population. The aim of this review was to document the implementation characteristics of remote supervision used including: (1) type of supervision such as synchronous, asynchronous supervision or mixed; (2) frequency and intensity of remote supervision; and (3) outcomes used to measure intervention delivery as well as effectiveness within this population. This scoping review follows EQUATOR Network recommendations for screening and extracting data. Results Twenty-six studies using a variety of remote supervision technology and outcome measures were included. Supervision frequency and intensity are poorly reported with no standardization. One hundred and six outcome measures were reported in this review showing large diversity in the areas being explored. Discussion Different types of remote supervision have been used with this population; however, there are no clear guidelines on clinical implementation. Future studies must better define implementation parameters of remote supervision. Benefit on physical activity, balance and mobility outcomes also need to be further explored.

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