Acute biochemical diagnostics of mild traumatic brain injury : A clinical study

Traumatic brain injury (TBI) is a global health burden. Most cases diagnosed with TBI are mild traumatic brain injury (mTBI), however, no unanimous definition of mTBI exists. Although most of the patients with mTBI recover well, a group of patients develop persistent post-injury symptoms. Blood biomarkers could be used as the surrogate markers of injury and could assist in assessing the true severity and prognosis of the eventual brain damage. Three studies were conducted for this project. Firstly, blood levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) were analysed in patients with orthopedic trauma without any central nervous system (CNS) insults compared to patients with computed tomography (CT)-negative mTBI at multiple time points after admission and during follow-up visits. The second study correlated the admission levels (≤24 hours) of GFAP and neurofilament light (NF-L) with outcome in patients with mTBI to explore the prediction abilities of these blood biomarkers. In the last study, the prognostic value of the neurodegenerative biomarkers, total tau (T-tau) and β-amyloid isoforms 1–40 (Aβ40), and 1–42 (Aβ42) were investigated using admission samples. Combinations of biomarkers panels were formed to study the sensitivity and specificity of these biomarkers for outcome prediction (studies II and III). A multiparameter panel including the clinical parameters and blood biomarkers was devised to study the best prediction model (study III). This project, focusing on the acute biochemical diagnostics of mTBI, reported that GFAP and UCH-L1 are not specific biomarkers for CT-negative mTBI. However, we found that the early levels of GFAP and NF-L are significantly correlated with the outcome in patients with mTBI. The admission level of NF-L has a significant predictive value for mTBI, also in a multi-variate model. Finally, the admission levels of T-tau were significantly correlated with the outcome in patients with mTBI.Lievän tapaturmaisen aivovamman biokemiallinen diagnostiikka Tapaturmaiset aivovammat ovat maailmanlaajuinen terveysongelma. Suurin osa aivovammoista on lieviä. Suurin osa lievän aivovamman saaneista potilaista toipuu hyvin, mutta osalle jää vammasta kuitenkin pitkäaikaisia jälkioireita. Verestä mitattavia merkkiaineita, biomarkkereita, voidaan käyttää mahdollisesti apuna aivovamman vakavuuden, aivovaurion luonteen ja potilaan toipumisennusteen arvioinnissa. Tähän väitöskirjahankkeeseen kuuluu kolme kliinistä tutkimusta. Ensimmäisessä analysoitiin gliaalisen fibrillaarisen happaman proteiinin (GFAP) ja ubikitiini-karboksiterminaalisen hydrolaasi L1:n (UCH-L1) veripitoisuudet ortopedisen vamman saaneilla potilailta, joilla ei ollut taustallaan aivovammaa tai muuta aivotapahtumaa, ja vertasimme niitä lievän aivovamman saaneiden potilaiden vastaaviin veripitoisuuksiin. Näillä aivovammapotilailla ei ollut poikkeavia löydöksiä pään tietokonetomografiassa (TT) eli he olivat TT-negatiivisia. Toisessa tutkimuksessa analysoitiin lievän aivovamman saaneilta potilailta 24 tunnin kuluessa sairaalaan saapumisesta veren GFAP:n ja kevyen neurofilamentti -proteiinin (NF-L) pitoisuudet, ja tutkittiin niiden korrelaatiota potilaiden myöhempään toipumisen tasoon. Kolmannessa tutkimuksessa analysoitiin kokonais-taun, beeta-amyloidi 1– 40:n (Aβ40) ja beeta-amyloidi 1–42:n (Aβ42) veripitoisuudet lievän aivovamman saaneilta potilailta 24 tunnin kuluessa sairaalaan saapumisesta. Jälleen tutkittiin merkkiaineiden ennustearvoa myöhemmän toipumisen tason suhteen. Tämän lievien tapaturmaisten aivovammojen biokemiallista diagnostiikkaa tutkivan väitöskirjahankkeen tärkeimmät löydökset ovat: i) verestä mitattujen GFAP:n ja UCH-L1:n pitoisuudet eivät ole spesifejä lievälle TT-negatiiviselle aivovammalle, ii) sairaalaan saapumisvaiheessa mitatut GFAP:n ja NF-L:n veripitoisuudet korreloivat merkittävästi lievän aivovamman toipumisennusteen kanssa, ja iii) sairaalaan saapumisvaiheen kokonais-taun, Aβ40:n ja Aβ42:n veripitoisuuksilla ei kyetä ennustamaan lievän aivovamman saaneen potilaan toipumista

Tau as a fluid biomarker of concussion and neurodegeneration

Concussion is predominant among the vast number of traumatic brain injuries that occur worldwide. Difficulties in timely identification, whether concussion led to neuronal injury or not, diagnosis and the lack of prognostic tools for adequate management could lead this type of brain injury to progressive neurodegenerative diseases. Tau has been extensively studied in recent years, particularly in repetitive mild traumatic brain injuries and sports-related concussions. Tauopathies, the group of neurodegenerative diseases, have also been studied with advanced functional imaging. Nevertheless, neurodegenerative diseases, such as chronic traumatic encephalopathy, are still conclusively diagnosed at autopsy. Here, we discuss the diagnostic dilemma and the relationship between concussion and neurodegenerative diseases and review the literature on tau as a promising biomarker for concussion

Huge variability in restrictions of mobilization for patients with aneurysmal subarachnoid hemorrhage - A European survey of practice.

INTRODUCTION One of the major goals of neurointensive care is to prevent secondary injuries following aSAH. Bed rest and patient immobilization are practiced in order to decrease the risk of DCI. RESEARCH QUESTION To explore the current practices in place concerning the management of patients with aSAH, specifically, protocols and habits regarding restrictions of mobilization and HOB positioning. MATERIAL AND METHODS A survey was designed, modified, and approved by the panel of the Trauma & Critical Care section of the EANS to cover the practice of restrictions of patient mobilization and HOB positioning in patients with aSAH. RESULTS Twenty-nine physicians from 17 countries completed the questionnaire. The majority (79.3%) stated that non-secured aneurysm and the presence of an EVD were the factors related to the establishment of restriction of mobilization. The average duration of the restriction varied widely ranging between 1 and 21 days. The presence of an EVD (13.8%) was found to be the main reason to recommend restriction of HOB elevation. The average duration of restriction of HOB positioning ranged between 3 and 14 days. Rebleeding or complications related to CSF over-drainage were found to be related to these restrictions. DISCUSSION AND CONCLUSION Restriction of patient mobilization regimens vary widely in Europe. Current limited evidence does not support an increased risk of DCI rather the early mobilization might be beneficial. Large prospective studies and/or the initiative of a RCT are needed to understand the significance of early mobilization on the outcome of patients with aSAH

Trajectories of interleukin 10 and heart fatty acid-binding protein levels in traumatic brain injury patients with or without extracranial injuries

BackgroundInterleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have gained interest as diagnostic biomarkers of traumatic brain injury (TBI), but factors affecting their blood levels in patients with moderate-to-severe TBI are largely unknown.ObjectiveTo investigate the trajectories of IL-10 and H-FABP between TBI patients with and without extracranial injuries (ECI); to investigate if there is a correlation between the levels of IL-10 and H-FABP with the levels of inflammation/infection markers C-reactive protein (CRP) and leukocytes; and to investigate if there is a correlation between the admission level of H-FABP with admission levels of cardiac injury markers, troponin (TnT), creatine kinase (CK), and creatine kinase MB isoenzyme mass (CK-MBm).Materials and methodsThe admission levels of IL-10, H-FABP, CRP, and leukocytes were measured within 24 h post-TBI and on days 1, 2, 3, and 7 after TBI. The admission levels of TnT, CK, and CK-MBm were measured within 24 h post-TBI.ResultsThere was a significant difference in the concentration of H-FABP between TBI patients with and without ECI on day 0 (48.2 ± 20.5 and 12.4 ± 14.7 ng/ml, p = 0.02, respectively). There was no significant difference in the levels of IL-10 between these groups at any timepoints. There was a statistically significant positive correlation between IL-10 and CRP on days 2 (R = 0.43, p < 0.01) and 7 (R = 0.46, p = 0.03) after injury, and a negative correlation between H-FABP and CRP on day 0 (R = -0.45, p = 0.01). The levels of IL-10 or H-FABP did not correlate with leukocyte counts at any timepoint. The admission levels of H-FABP correlated with CK (R = 0.70, p < 0.001) and CK-MBm (R = 0.61, p < 0.001), but not with TnT.ConclusionInflammatory reactions during the early days after a TBI do not significantly confound the use of IL-10 and H-FABP as TBI biomarkers. Extracranial injuries and cardiac sources may influence the levels of H-FABP in patients with moderate-to-severe TBI

Interleukin 10 and Heart Fatty Acid-Binding Protein as Early Outcome Predictors in Patients With Traumatic Brain Injury

Background: Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions. Aim: To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100β, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors. Methods: Blood samples from patients with acute TBI (all severities) were collected &lt;24 h post trauma. The outcome was measured &gt;6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities. Results: When sensitivity was set at 95-100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities. Conclusion: Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100β and clinical parameters improves outcome prediction models in TBI.</p

INTERLEUKIN 10 AND HEART FATTY-ACID BINDING PROTEIN AS EARLY OUTCOME PREDICTORS IN PATIENTS WITH TRAUMATIC BRAIN INJURY

Background: Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions. Aim: To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100β, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors. Methods: Blood samples from patients with acute TBI (all severities) were collected 6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities. Results: When sensitivity was set at 95–100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities. Conclusion: Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100β and clinical parameters improves outcome prediction models in TBI

Admission Levels of Total Tau and β-Amyloid Isoforms 1–40 and 1–42 in Predicting the Outcome of Mild Traumatic Brain Injury

Background: The purpose of this study was to investigate if admission levels of total tau (T-tau) and β-amyloid isoforms 1-40 (Aβ40) and 1-42 (Aβ42) could predict clinical outcome in patients with mild traumatic brain injury (mTBI). Methods: A total of 105 patients with mTBI [Glasgow Coma Scale (GCS) ≥ 13] recruited in Turku University Hospital, Turku, Finland were included in this study. Blood samples were drawn within 24 h of admission for analysis of plasma T-tau, Aβ40, and Aβ42. Patients were divided into computed tomography (CT)-positive and CT-negative groups. The outcome was assessed 6–12 months after the injury using the Extended Glasgow Outcome Scale (GOSE). Outcomes were defined as complete (GOSE 8) or incomplete (GOSE < 8) recovery. The Rivermead Post Concussion Symptoms Questionnaire (RPCSQ) was also used to assess mTBI-related symptoms. Predictive values of the biomarkers were analyzed independently, in panels and together with clinical parameters. Results: The admission levels of plasma T-tau, Aβ40, and Aβ42 were not significantly different between patients with complete and incomplete recovery. The levels of T-tau, Aβ40, and Aβ42 could poorly predict complete recovery, with areas under the receiver operating characteristic curve 0.56, 0.52, and 0.54, respectively. For the whole cohort, there was a significant negative correlation between the levels of T-tau and ordinal GOSE score (Spearman ρ = −0.231, p = 0.018). In a multivariate logistic regression model including age, GCS, duration of posttraumatic amnesia, Injury Severity Score (ISS), time from injury to sampling, and CT findings, none of the biomarkers could predict complete recovery independently or together with the other two biomarkers. Plasma levels of T-tau, Aβ40, and Aβ42 did not significantly differ between the outcome groups either within the CT-positive or CT-negative subgroups. Levels of Aβ40 and Aβ42 did not significantly correlate with outcome, but in the CT-positive subgroup, the levels of T-tau significantly correlated with ordinal GOSE score (Spearman ρ = −0.288, p = 0.035). The levels of T-tau, Aβ40, and Aβ42 were not correlated with the RPCSQ scores. Conclusions: The early levels of T-tau are correlated with the outcome in patients with mTBI, but none of the biomarkers either alone or in any combinations could predict complete recovery in patients with mTBI

Trajectories of interleukin 10 and heart fatty acid-binding protein levels in traumatic brain injury patients with or without extracranial injuries

Background: Interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have gained interest as diagnostic biomarkers of traumatic brain injury (TBI), but factors affecting their blood levels in patients with moderate-to-severe TBI are largely unknown. Objective: To investigate the trajectories of IL-10 and H-FABP between TBI patients with and without extracranial injuries (ECI); to investigate if there is a correlation between the levels of IL-10 and H-FABP with the levels of inflammation/infection markers C-reactive protein (CRP) and leukocytes; and to investigate if there is a correlation between the admission level of H-FABP with admission levels of cardiac injury markers, troponin (TnT), creatine kinase (CK), and creatine kinase MB isoenzyme mass (CK-MBm). Materials and methods: The admission levels of IL-10, H-FABP, CRP, and leukocytes were measured within 24 h post-TBI and on days 1, 2, 3, and 7 after TBI. The admission levels of TnT, CK, and CK-MBm were measured within 24 h post-TBI. Results: There was a significant difference in the concentration of H-FABP between TBI patients with and without ECI on day 0 (48.2 ± 20.5 and 12.4 ± 14.7 ng/ml, p = 0.02, respectively). There was no significant difference in the levels of IL-10 between these groups at any timepoints. There was a statistically significant positive correlation between IL-10 and CRP on days 2 (R = 0.43, p < 0.01) and 7 (R = 0.46, p = 0.03) after injury, and a negative correlation between H-FABP and CRP on day 0 (R = -0.45, p = 0.01). The levels of IL-10 or H-FABP did not correlate with leukocyte counts at any timepoint. The admission levels of H-FABP correlated with CK (R = 0.70, p < 0.001) and CK-MBm (R = 0.61, p < 0.001), but not with TnT. Conclusion: Inflammatory reactions during the early days after a TBI do not significantly confound the use of IL-10 and H-FABP as TBI biomarkers. Extracranial injuries and cardiac sources may influence the levels of H-FABP in patients with moderate-to-severe TBI.publishedVersionPeer reviewe

Potential of heart fatty-acid binding protein, neurofilament light, interleukin-10 and S100 calcium-binding protein B in the acute diagnostics and severity assessment of traumatic brain injury

Background: There is substantial interest in blood biomarkers as fast and objective diagnostic tools for traumatic brain injury (TBI) in the acute setting.Methods: Adult patients (≥18) with TBI of any severity and indications for CT scanning and orthopaedic injury controls were prospectively recruited during 2011-2013 at Turku University Hospital, Finland. The severity of TBI was classified with GCS: GCS 13-15 was classified as mild (mTBI); GCS 9-12 as moderate (moTBI) and GCS 3-8 as severe (sTBI). Serum samples were collected within 24 hours of admission and biomarker levels analysed with high-performance kits. The ability of biomarkers to distinguish between severity of TBI and CT-positive and CT-negative patients was assessed.Results: Among 189 patients recruited, neurofilament light (NF-L) was obtained from 175 patients with TBI and 40 controls. S100 calcium-binding protein B (S100B), heart fatty-acid binding protein (H-FABP) and interleukin-10 (IL-10) were analysed for 184 patients with TBI and 39 controls. There were statistically significant differences between levels of all biomarkers between the severity classes, but none of the biomarkers distinguished patients with moTBI from patients with sTBI. Patients with mTBI discharged from the ED had lower levels of IL-10 (0.26, IQR=0.21, 0.39 pg/mL), H-FABP (4.15, IQR=2.72, 5.83 ng/mL) and NF-L (8.6, IQR=6.35, 15.98 pg/mL) compared with those admitted to the neurosurgical ward, IL-10 (0.55, IQR=0.31, 1.42 pg/mL), H-FABP (6.022, IQR=4.19, 20.72 ng/mL) and NF-L (13.95, IQR=8.33, 19.93 pg/mL). We observed higher levels of H-FABP and NF-L in older patients with mTBI. None of the biomarkers or their combinations was able to distinguish CT-positive (n=36) or CT-negative (n=58) patients with mTBI from controls.Conclusions: S100B, H-FABP, NF-L and IL-10 levels in patients with mTBI were significantly lower than in patients with moTBI and sTBI but alone or in combination, were unable to distinguish patients with mTBI from orthopaedic controls. This suggests these biomarkers cannot be used alone to diagnose mTBI in trauma patients in the acute setting.</p

Interleukin 10 and Heart Fatty Acid-Binding Protein as Early Outcome Predictors in Patients With Traumatic Brain Injury

Background:Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions. Aim:To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100 beta, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors. Methods:Blood samples from patients with acute TBI (all severities) were collected 6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE >= 5)/unfavorable outcome (GOSE <= 4) and complete (GOSE = 8)/incomplete (GOSE <= 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities. Results:When sensitivity was set at 95-100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities. Conclusion:Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100 beta and clinical parameters improves outcome prediction models in TBI