| 1. |
- Büki, Andras, 1966-, et al.
(författare)
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Minor and repetitive head injury
- 2014
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Ingår i: Advances and Technical Standards in Neurosurgery. - Cham : Springer. - 9783319090658 - 9783319090665 ; , s. 147-192
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Bokkapitel (refereegranskat)abstract
- Traumatic brain injury (TBI) is the leading cause of death and disability in the young, active population and expected to be the third leading cause of death in the whole world until 2020. The disease is frequently referred to as the silent epidemic, and many authors highlight the "unmet medical need" associated with TBI.The term traumatically evoked brain injury covers a heterogeneous group ranging from mild/minor/minimal to severe/non-salvageable damages. Severe TBI has long been recognized to be a major socioeconomical health-care issue as saving young lives and sometimes entirely restituting health with a timely intervention can indeed be extremely cost efficient.Recently it has been recognized that mild or minor TBI should be considered similarly important because of the magnitude of the patient population affected. Other reasons behind this recognition are the association of mild head injury with transient cognitive disturbances as well as long-term sequelae primarily linked to repeat (sport-related) injuries.The incidence of TBI in developed countries can be as high as 2-300/100,000 inhabitants; however, if we consider the injury pyramid, it turns out that severe and moderate TBI represents only 25-30 % of all cases, while the overwhelming majority of TBI cases consists of mild head injury. On top of that, or at the base of the pyramid, are the cases that never show up at the ER - the unreported injuries.Special attention is turned to mild TBI as in recent military conflicts it is recognized as "signature injury."This chapter aims to summarize the most important features of mild and repetitive traumatic brain injury providing definitions, stratifications, and triage options while also focusing on contemporary knowledge gathered by imaging and biomarker research.Mild traumatic brain injury is an enigmatic lesion; the classification, significance, and its consequences are all far less defined and explored than in more severe forms of brain injury.Understanding the pathobiology and pathomechanisms may aid a more targeted approach in triage as well as selection of cases with possible late complications while also identifying the target patient population where preventive measures and therapeutic tools should be applied in an attempt to avoid secondary brain injury and late complications.
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| 2. |
- Kobeissy, Firas, et al.
(författare)
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Glycomic and Glycoproteomic Techniques in Neurodegenerative Disorders and Neurotrauma : Towards Personalized Markers
- 2022
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 11:3
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Forskningsöversikt (refereegranskat)abstract
- The proteome represents all the proteins expressed by a genome, a cell, a tissue, or an organism at any given time under defined physiological or pathological circumstances. Proteomic analysis has provided unparalleled opportunities for the discovery of expression patterns of proteins in a biological system, yielding precise and inclusive data about the system. Advances in the proteomics field opened the door to wider knowledge of the mechanisms underlying various post-translational modifications (PTMs) of proteins, including glycosylation. As of yet, the role of most of these PTMs remains unidentified. In this state-of-the-art review, we present a synopsis of glycosylation processes and the pathophysiological conditions that might ensue secondary to glycosylation shortcomings. The dynamics of protein glycosylation, a crucial mechanism that allows gene and pathway regulation, is described. We also explain how-at a biomolecular level-mutations in glycosylation-related genes may lead to neuropsychiatric manifestations and neurodegenerative disorders. We then analyze the shortcomings of glycoproteomic studies, putting into perspective their downfalls and the different advanced enrichment techniques that emanated to overcome some of these challenges. Furthermore, we summarize studies tackling the association between glycosylation and neuropsychiatric disorders and explore glycoproteomic changes in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington disease, multiple sclerosis, and amyotrophic lateral sclerosis. We finally conclude with the role of glycomics in the area of traumatic brain injury (TBI) and provide perspectives on the clinical application of glycoproteomics as potential diagnostic tools and their application in personalized medicine.
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| 3. |
- Mondello, Stefania, et al.
(författare)
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Circulating brain injury exosomal proteins following Moderate-to-Severe traumatic brain injury : temporal profile, outcome prediction and therapy implications
- 2020
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Mondello, Stefania, et al.
(författare)
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CSF and Plasma Amyloid-β Temporal Profiles and Relationships with Neurological Status and Mortality after Severe Traumatic Brain Injury
- 2014
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- The role of amyloid-beta (A beta) neuropathology and its significant changes in biofluids after traumatic brain injury (TBI) is still debated. We used ultrasensitive digital ELISA approach to assess amyloid-beta(1-42) (A beta 42) concentrations and time-course in cerebrospinal fluid (CSF) and in plasma of patients with severe TBI and investigated their relationship to injury characteristics, neurological status and clinical outcome. We found decreased CSF A beta 42 levels in TBI patients acutely after injury with lower levels in patients who died 6 months post-injury than in survivors. Conversely, plasma A beta 42 levels were significantly increased in TBI with lower levels in patients who survived. A trend analysis showed that both CSF and plasma A beta 42 levels strongly correlated with mortality. A positive correlation between changes in CSF A beta 42 concentrations and neurological status as assessed by Glasgow Coma Scale (GCS) was identified. Our results suggest that determination of A beta 42 may be valuable to obtain prognostic information in patients with severe TBI as well as in monitoring the response of the brain to injury.
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| 5. |
- Mondello, Stefania, et al.
(författare)
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Exploring serum glycome patterns after moderate to severe traumatic brain injury : A prospective pilot study
- 2022
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Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 50
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glycans play essential functional roles in the nervous system and their pathobiological relevance has become increasingly recognized in numerous brain disorders, but not fully explored in traumatic brain injury (TBI). We investigated longitudinal glycome patterns in patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) to characterize glyco-biomarker signatures and their relation to clinical features and long-term outcome.Methods: This prospective single-center observational study included 51 adult patients with TBI (GCS ≤12) admitted to the neurosurgical unit of the University Hospital of Pecs, Pecs, Hungary, between June 2018 and April 2019. We used a high-throughput liquid chromatography-tandem mass spectrometry platform to assess serum levels of N-glycans up to 3 days after injury. Outcome was assessed using the Glasgow Outcome Scale-Extended (GOS-E) at 12 months post-injury. Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, were used to analyze glycomics data and define highly influential structures driving class distinction. Receiver operating characteristic analyses were used to determine prognostic accuracy.Findings: We identified 94 N-glycans encompassing all typical structural types, including oligomannose, hybrid, and complex-type entities. Levels of high mannose, hybrid and sialylated structures were temporally altered (p<0·05). Four influential glycans were identified. Two brain-specific structures, HexNAc5Hex3DeoxyHex0NeuAc0 and HexNAc5Hex4DeoxyHex0NeuAc1, were substantially increased early after injury in patients with unfavorable outcome (GOS-E≤4) (area under the curve [AUC]=0·75 [95%CI 0·59-0·90] and AUC=0·71 [0·52-0·89], respectively). Serum levels of HexNAc7Hex7DeoxyHex1NeuAc2 and HexNAc8Hex6DeoxyHex0NeuAc0 were persistently increased in patients with favorable outcome, but undetectable in those with unfavorable outcome. Levels of HexNAc5Hex4DeoxyHex0NeuAc1 were acutely elevated in patients with mass lesions and in those requiring decompressive craniectomy.Interpretation: In spite of the exploratory nature of the study and the relatively small number of patients, our results provide to the best of our knowledge initial evidence supporting the utility of glycomics approaches for biomarker discovery and patient phenotyping in TBI. Further larger multicenter studies will be required to validate our findings and to determine their pathobiological value and potential applications in practice.
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| 6. |
- Mondello, Stefania, et al.
(författare)
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Extracellular vesicles : pathogenetic, diagnostic and therapeutic value in traumatic brain injury
- 2018
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Ingår i: Expert Review of Proteomics. - : Taylor & Francis. - 1478-9450 .- 1744-8387. ; 15:5, s. 451-461
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Forskningsöversikt (refereegranskat)abstract
- Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Accurate classification according to injury-specific and patient-specific characteristics is critical to help informed clinical decision-making and to the pursuit of precision medicine in TBI. Reliable biomarker signatures for improved TBI diagnostics are required but still an unmet need. Areas covered: Extracellular vesicles (EVs) represent a new class of biomarker candidates in TBI. These nano-sized vesicles have key roles in cell signaling profoundly impacting pathogenic pathways, progression and long-term sequelae of TBI. As such EVs might provide novel neurobiological insights, enhance our understanding of the molecular mechanisms underlying TBI pathophysiology and recovery, and serve as biomarker signatures and therapeutic targets and delivery systems. Expert commentary: EVs are fast gaining momentum in TBI research, paving the way for new transformative diagnostic and treatment approaches. Their potential to sort out TBI variability and active involvement in the mechanisms underpinning different clinical phenotypes point out unique opportunities for improved classification, risk-stratification ad intervention, harboring promise of predictive, personalized, and even preemptive therapeutic strategies. Although a great deal of progress has been made, substantial efforts are still required to ensure the needed rigorous validation and reproducibility for clinical implementation of EVs.
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| 7. |
- Mondello, Stefania, et al.
(författare)
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The Challenge of Mild Traumatic Brain Injury : Role of Biochemical Markers in Diagnosis of Brain Damage
- 2013
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Ingår i: Medicinal research reviews (Print). - : John Wiley & Sons. - 0198-6325 .- 1098-1128. ; 34:3, s. 503-531
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Forskningsöversikt (refereegranskat)abstract
- During the past decade there has been an increasing recognition of the incidence of mildtraumatic brain injury (mTBI) and a better understanding of the subtle neurological and cognitive deficitsthat may result from it. A substantial, albeit suboptimal, effort has been made to define diagnostic criteriafor mTBI and improve diagnostic accuracy. Thus, biomarkers that can accurately and objectively detectbrain injury after mTBI and, ideally, aid in clinical management are needed. In this review, we discuss thecurrent research on serum biomarkers for mTBI including their rationale and diagnostic performances.Sensitive and specific biomarkers reflecting brain injury can provide important information regardingTBI pathophysiology and serve as candidate markers for predicting abnormal computed tomographyfindings and/or the development of residual deficits in patients who sustain an mTBI. We also outline theroles of biomarkers in settings of specific interest including pediatric TBI, sports concussions and militaryinjuries, and provide perspectives on the validation of such markers for use in the clinic. Finally, emergingproteomics-based strategies for identifying novel markers will be discussed.
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| 8. |
- Trivedi, Dhanisha, 1993-, et al.
(författare)
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Screening Performance of S100 Calcium-Binding Protein B, Glial Fibrillary Acidic Protein, and Ubiquitin C-Terminal Hydrolase L1 for Intracranial Injury Within Six Hours of Injury and Beyond
- 2024
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 41:3-4, s. 349-358
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The Scandinavian NeuroTrauma Committee (SNC) guidelines recommend S100B as a screening tool for early detection of Traumatic brain injury (TBI) in patients presenting with an initial Glasgow coma scale (GCS) of 14-15. The objective of the current study was to compare S100B's diagnostic performance within the recommended 6-hour window after injury, compared to GFAP and UCH-L1. The secondary outcome of interest was the ability of these biomarkers in detecting traumatic intracranial pathology beyond the 6-hour mark.METHODS: The Center-TBI core database (2014-2017) was queried for data pertaining to all TBI patients with an initial GCS of 14-15 who had a blood sample taken within 6 hours of injury in which the levels of S100B, GFAP, and UCH-L1 were measured. As a subgroup analysis, data involving patients with blood samples taken within 6-9 hours, and 9-12 hours were analyzed separately for diagnostic ability. The diagnostic ability of these biomarkers for detecting any intracranial injury was evaluated based on the area under the receiver operating characteristic curve (AUC). Each biomarker's sensitivity, specificity, and accuracy were also reported at the cutoff that maximized Youden's index.RESULTS: A total of 531 TBI patients with GCS 14-15 on admission had a blood sample taken within 6 hours, of whom 24.9% (N = 132) had radiologically confirmed intracranial injury. The AUCs of GFAP (0.86, 95% confidence interval (CI): 0.82-0.90) and UCH-L1 (0.81, 95% CI: 0.76-0.85) were statistically significantly higher than that of S100B (0.74, 95% CI: 0.69-0.79) during this time. There was no statistically significant difference in the predictive ability of S100B when sampled within 6 hours, 6-9 hours, and 9-12 hours of injury, as the p-values were >0.05 when comparing the AUCs. Overlapping AUC 95% CI suggests no benefit of a combined GFAP and UCH-L1 screening tool over GFAP during the time periods studied [ 0.87 (0.83-0.90) vs 0.86 (0.82-0.90) when sampled within 6 hours of injury, 0.83 (0.78-0.88) vs 0.83 (0.78-0.89) within 6-to-9 hours and 0.81 (0.73-0.88) vs 0.79 (0.72-0.87) within 9-12 hours].CONCLUSIONS: Targeted analysis of the CENTER-TBI core database, with focus on the patient category for which biomarker testing is recommended by the SNC guidelines, revealed that GFAP and UCH-L1 perform superior to S100B in predicting CT-positive intracranial lesions within 6 hours of injury. GFAP continued to exhibit superior predictive ability to S100B during the time periods studied. S100B displayed relatively unaltered screening performance beyond the diagnostic timeline provided by SNC guidelines. These findings suggest the need for a re-evaluation of the current SNC TBI guidelines.
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| 9. |
- Wang, Kevin K., et al.
(författare)
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Blood-based traumatic brain injury biomarkers : Clinical utilities and regulatory pathways in the United States, Europe and Canad
- 2021
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Ingår i: Expert Review of Molecular Diagnostics. - : Expert Reviews Ltd.. - 1473-7159 .- 1744-8352. ; 21:12, s. 1303-1321
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Traumatic brain injury (TBI) is a major global health issue, resulting in debilitating consequences to families, communities, and health-care systems. Prior research has found that biomarkers aid in the pathophysiological characterization and diagnosis of TBI. Significantly, the FDA has recently cleared both a bench-top assay and a rapid point-of-care assays of tandem biomarker (UCH-L1/GFAP)-based blood test to aid in the diagnosis mTBI patients. With the global necessity of TBI biomarkers research, several major consortium multicenter observational studies with biosample collection and biomarker analysis have been created in the USA, Europe, and Canada. As each geographical region regulates its data and findings, the International Initiative for Traumatic Brain Injury Research (InTBIR) was formed to facilitate data integration and dissemination across these consortia.Areas covered: This paper covers heavily investigated TBI biomarkers and emerging non-protein markers. Finally, we analyze the regulatory pathways for converting promising TBI biomarkers into approved in-vitro diagnostic tests in the United States, European Union, and Canada.Expert opinion: TBI biomarker research has significantly advanced in the last decade. The recent approval of an iSTAT point of care test to detect mild TBI has paved the way for future biomarker clearance and appropriate clinical use across the globe.
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| 10. |
- Zhang, Zhiqun, et al.
(författare)
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Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products
- 2014
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Ingår i: PLOS ONE. - San Francisco, USA : Public Library of Science (PLoS). - 1932-6203. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain injuries is recognized but not well understood. In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoantibodies showed predominant immunoreactivity against a cluster of bands from 38-50 kDa on human brain immunoblots, which were identified as GFAP and GFAP breakdown products. GFAP autoantibody levels increased by 7 days after injury, and were of the IgG subtype predominantly. Results from in vitro tests and rat TBI experiments also indicated that calpain was responsible for removing the amino and carboxyl termini of GFAP to yield a 38 kDa fragment. Additionally, TBI autoantibody staining co-localized with GFAP in injured rat brain and in primary rat astrocytes. These results suggest that GFAP breakdown products persist within degenerating astrocytes in the brain. Anti-GFAP autoantibody also can enter living astroglia cells in culture and its presence appears to compromise glial cell health. TBI patients showed an average 3.77 fold increase in anti-GFAP autoantibody levels from early (0-1 days) to late (7-10 days) times post injury. Changes in autoantibody levels were negatively correlated with outcome as measured by GOS-E score at 6 months, suggesting that TBI patients with greater anti-GFAP immune-responses had worse outcomes. Due to the long lasting nature of IgG, a test to detect anti-GFAP autoantibodies is likely to prolong the temporal window for assessment of brain damage in human patients.
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