Outlier Analysis for Acute Blood Biomarkers of Moderate and Severe Traumatic Brain Injury.

Blood biomarkers have been studied to improve the clinical assessment and prognostication of patients with moderate-severe traumatic brain injury (mo/sTBI). To assess their clinical usability, one needs to know of potential factors that might cause outlier values and affect clinical decision making. In a prospective study, we recruited patients with mo/sTBI (n = 85) and measured the blood levels of eight protein brain pathophysiology biomarkers, including glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), neurofilament light (Nf-L), heart-type fatty acid-binding protein (H-FABP), interleukin-10 (IL-10), total tau (T-tau), amyloid ß40 (Aß40) and amyloid ß42 (Aß42), within 24 h of admission. Similar analyses were conducted for controls (n = 40) with an acute orthopedic injury without any head trauma. The patients with TBI were divided into subgroups of normal versus abnormal (n = 9/76) head computed tomography (CT) and favorable (Glasgow Outcome Scale Extended [GOSE] 5-8) versus unfavorable (GOSE <5) (n = 38/42, 5 missing) outcome. Outliers were sought individually from all subgroups from and the whole TBI patient population. Biomarker levels outside Q1 - 1.5 interquartile range (IQR) or Q3 + 1.5 IQR were considered as outliers. The medical records of each outlier patient were reviewed in a team meeting to determine possible reasons for outlier values. A total of 29 patients (34%) combined from all subgroups and 12 patients (30%) among the controls showed outlier values for one or more of the eight biomarkers. Nine patients with TBI and five control patients had outlier values in more than one biomarker (up to 4). All outlier values were > Q3 + 1.5 IQR. A logical explanation was found for almost all cases, except the amyloid proteins. Explanations for outlier values included extremely severe injury, especially for GFAP and S100B. In the case of H-FABP and IL-10, the explanation was extracranial injuries (thoracic injuries for H-FABP and multi-trauma for IL-10), in some cases these also were associated with abnormally high S100B. Timing of sampling and demographic factors such as age and pre-existing neurological conditions (especially for T-tau), explained some of the abnormally high values especially for Nf-L. Similar explanations also emerged in controls, where the outlier values were caused especially by pre-existing neurological diseases. To utilize blood-based biomarkers in clinical assessment of mo/sTBI, very severe or fatal TBIs, various extracranial injuries, timing of sampling, and demographic factors such as age and pre-existing systemic or neurological conditions must be taken into consideration. Very high levels seem to be often associated with poor prognosis and mortality (GFAP and S100B).

Late Blood Levels of Neurofilament Light Correlate With Outcome in Patients With Traumatic Brain Injury.

Neurofilament light (NF-L) is an axonal protein that has shown promise as a traumatic brain injury (TBI) biomarker. Serum NF-L shows a rather slow rise after injury, peaking after 1-2 weeks, although some studies suggest that it may remain elevated for months after TBI. The aim of this study was to examine if plasma NF-L levels several months after the injury correlate with functional outcome in patients who have sustained TBIs of variable initial severity. In this prospective study of 178 patients with TBI and 40 orthopedic injury controls, we measured plasma NF-L levels in blood samples taken at the follow-up appointment on average 9 months after injury. Patients with TBI were divided into two groups (mild [mTBI] vs. moderate-to-severe [mo/sTBI]) according to the severity of injury assessed with the Glasgow Coma Scale upon admission. Recovery and functional outcome were assessed using the Extended Glasgow Outcome Scale (GOSE). Higher levels of NF-L at the follow-up correlated with worse outcome in patients with moderate-to-severe TBI (Spearman's rho = -0.18; p < 0.001). In addition, in computed tomography-positive mTBI group, the levels of NF-L were significantly lower in patients with GOSE 7-8 (median 18.14; interquartile range [IQR] 9.82, 32.15) when compared with patients with GOSE <7 (median 73.87; IQR 32.17, 110.54; p = 0.002). In patients with mTBI, late NF-L levels do not seem to provide clinical benefit for late-stage assessment, but in patients with initially mo/sTBI, persistently elevated NF-L levels are associated with worse outcome after TBI and may reflect ongoing brain injury.

Outcome and survival of surgically treated acute subdural hematomas and postcraniotomy hematomas - A retrospective cohort study.

Background: The morbidity and mortality of acute subdural hematoma (aSDH) remains high. Several factors have been reported to affect the outcome and survival of these patients. In this study, we explored factors potentially associated with the outcome and survival of surgically treated acute subdural hematoma (aSDH), including postcraniotomy hematomas (PCHs). Methods: This retrospective cohort study was conducted in a single tertiary university hospital between 2008 and 2012 and all aSDH patients that underwent surgical intervention were included. A total of 132 cases were identified for collection of demographics, clinical, laboratory, and imaging data. Univariate and multivariable analyses were performed to assess factors associated with three-month Glasgow Outcome Scale (GOS) and survival at one- and five-year. Results: In this study, PCH (n = 14, 10.6%) was not associated with a worse outcome according to the 3- month GOS (p = 0.37) or one (p = 0.34) and five-year (p = 0.37) survival. The multivariable analysis showed that the volume of initial hematoma (p = 0.009) and Abbreviated Injury Scale score (p = 0.016) were independent predictors of the three-month GOS. Glasgow Coma Scale (GCS) score (p < 0.001 and p = 0.037) and age (p = 0.048 and p = 0.003) were predictors for one and five-year survival, while use of antiplatelet drug (p = 0.030), neuroworsening (p = 0.005) and smoking (p = 0.026) were significant factors impacting one year survival. In addition, blood alcohol level on admission was a predictor for five-year survival (p = 0.025). Conclusions: These elucidations underscore that, although PCHs are pertinent, a comprehensive appreciation of multifarious variables is indispensable in aSDH prognosis. These findings are observational, not causal. Expanded research endeavors are advocated to corroborate these insights.

Plasma neurofilament light admission levels and development of axonal pathology in mild traumatic brain injury.

BACKGROUND: It is known that blood levels of neurofilament light (NF-L) and diffusion-weighted magnetic resonance imaging (DW-MRI) are both associated with outcome of patients with mild traumatic brain injury (mTBI). Here, we sought to examine the association between admission levels of plasma NF-L and white matter (WM) integrity in post-acute stage DW-MRI in patients with mTBI. METHODS: Ninety-three patients with mTBI (GCS ≥ 13), blood sample for NF-L within 24 h of admission, and DW-MRI ≥ 90 days post-injury (median = 229) were included. Mean fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated from the skeletonized WM tracts of the whole brain. Outcome was assessed using the Extended Glasgow Outcome Scale (GOSE) at the time of imaging. Patients were divided into CT-positive and -negative, and complete (GOSE = 8) and incomplete recovery (GOSE < 8) groups. RESULTS: The levels of NF-L and FA correlated negatively in the whole cohort (p = 0.002), in CT-positive patients (p = 0.016), and in those with incomplete recovery (p = 0.005). The same groups showed a positive correlation with mean MD, AD, and RD (p < 0.001-p = 0.011). In CT-negative patients or in patients with full recovery, significant correlations were not found. CONCLUSION: In patients with mTBI, the significant correlation between NF-L levels at admission and diffusion tensor imaging (DTI) measurements of diffuse axonal injury (DAI) over more than 3 months suggests that the early levels of plasma NF-L may associate with the presence of DAI at a later phase of TBI.

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.

Implementation of an Online External Ventricular Drain Training Module-An Educational Initiative to Improve Proficiency of Perioperative Health Care Providers: Results of a Retrospective Study.

BACKGROUND: An external ventricular drain (EVD) training module may improve the knowledge and proficiency of perioperative health care providers (HCPs). METHODS: We examined knowledge gaps, self-reported comfort in managing EVDs, and improvement in self-assessment scores among HCPs from 7 academic medical centers based on an online EVD training module. RESULTS: Of the 326 HCPs who completed the module, 207 (70.6%) reported being uncomfortable managing EVDs. The median pretest scores were 6 (interquartile range=2), and posttest scores were 8 (interquartile range=1), out of a maximum possible score of 9. The most frequent incorrectly answered questions were: (a) maximum allowed hourly cerebrospinal fluid volume drainage (51%), (b) the components of a normal intracranial pressure waveform (41%), and (c) identifying the correct position of the stopcock for accurate measurement of intracranial pressure (41%). The overall gain in scores was 2 (interquartile range=2) and highest among HCPs who had managed 1 to 25 EVDs (2.51, 95% confidence interval: 2.23-2.80), and without self-reported comfort in managing EVDs (2.26, 95% confidence interval: 1.96-2.33, P <0.0001). The majority of participants (312, 95.7%) reported that the training module helped them understand how to manage EVDs, and 276 (84.7%) rated the module 8 or more out of 10 in recommending it to their colleagues. CONCLUSIONS: This online EVD training module was well-received by participants. Overall, improved scores reflect enhanced knowledge among HCPs following completion of the module. The greatest benefit was observed in those reporting less experience and feeling uncomfortable in managing EVDs. The impact on the reduction in EVD-associated adverse events deserves further examination.

Post-acute blood biomarkers and disease progression in traumatic brain injury.

There is substantial interest in the potential for traumatic brain injury to result in progressive neurological deterioration. While blood biomarkers such as glial fibrillary acid protein (GFAP) and neurofilament light have been widely explored in characterizing acute traumatic brain injury (TBI), their use in the chronic phase is limited. Given increasing evidence that these proteins may be markers of ongoing neurodegeneration in a range of diseases, we examined their relationship to imaging changes and functional outcome in the months to years following TBI. Two-hundred and three patients were recruited in two separate cohorts; 6 months post-injury (n = 165); and >5 years post-injury (n = 38; 12 of whom also provided data ∼8 months post-TBI). Subjects underwent blood biomarker sampling (n = 199) and MRI (n = 172; including diffusion tensor imaging). Data from patient cohorts were compared to 59 healthy volunteers and 21 non-brain injury trauma controls. Mean diffusivity and fractional anisotropy were calculated in cortical grey matter, deep grey matter and whole brain white matter. Accelerated brain ageing was calculated at a whole brain level as the predicted age difference defined using T1-weighted images, and at a voxel-based level as the annualized Jacobian determinants in white matter and grey matter, referenced to a population of 652 healthy control subjects. Serum neurofilament light concentrations were elevated in the early chronic phase. While GFAP values were within the normal range at ∼8 months, many patients showed a secondary and temporally distinct elevations up to >5 years after injury. Biomarker elevation at 6 months was significantly related to metrics of microstructural injury on diffusion tensor imaging. Biomarker levels at ∼8 months predicted white matter volume loss at >5 years, and annualized brain volume loss between ∼8 months and 5 years. Patients who worsened functionally between ∼8 months and >5 years showed higher than predicted brain age and elevated neurofilament light levels. GFAP and neurofilament light levels can remain elevated months to years after TBI, and show distinct temporal profiles. These elevations correlate closely with microstructural injury in both grey and white matter on contemporaneous quantitative diffusion tensor imaging. Neurofilament light elevations at ∼8 months may predict ongoing white matter and brain volume loss over >5 years of follow-up. If confirmed, these findings suggest that blood biomarker levels at late time points could be used to identify TBI survivors who are at high risk of progressive neurological damage.

Structural Brain Connectivity Correlates with Outcome in Mild Traumatic Brain Injury.

We investigated the topology of structural brain connectivity networks and its association with outcome after mild traumatic brain injury, a major cause of permanent disability. Eighty-five patients with mild traumatic brain injury underwent magnetic resonance imaging (MRI) twice, about three weeks and eight months after injury, and 30 age-matched orthopedic trauma control subjects were scanned. Outcome was assessed with Extended Glasgow Outcome Scale on average eight months after injury. We performed constrained spherical deconvolution-based probabilistic streamlines tractography on diffusion MRI data and parcellated cortical and subcortical gray matter into 84 regions based on T1-weighted data to reconstruct structural brain connectivity networks weighted by the number of streamlines. Graph theoretical methods were employed to measure network properties in both patients and controls, and correlations between these properties and outcome were calculated. We found no global differences in the network properties between patients with mild traumatic brain injury and orthopedic control subjects at either stage. We found significantly increased betweenness centrality of the right pars opercularis in the chronic stage compared with control subjects, however. Further, both global and local network properties correlated significantly with outcome. Higher normalized global efficiency, degree, and strength as well as lower small-worldness were associated with better outcome. Correlations between the outcome and the local network properties were the most prominent in the left putamen and the left postcentral gyrus. Our results indicate that both global and local network properties provide valuable information about the outcome already in the acute/subacute stage and, therefore, are promising biomarkers for prognostic purposes in mild traumatic brain injury.

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.

Admission Levels of Interleukin 10 and Amyloid ß 1-40 Improve the Outcome Prediction Performance of the Helsinki Computed Tomography Score in Traumatic Brain Injury.

Background: Blood biomarkers may enhance outcome prediction performance of head computed tomography scores in traumatic brain injury (TBI). Objective: To investigate whether admission levels of eight different protein biomarkers can improve the outcome prediction performance of the Helsinki computed tomography score (HCTS) without clinical covariates in TBI. Materials and methods: Eighty-two patients with computed tomography positive TBIs were included in this study. Plasma levels of ß-amyloid isoforms 1-40 (Aß40) and 1-42 (Aß42), glial fibrillary acidic protein, heart fatty acid-binding protein, interleukin 10 (IL-10), neurofilament light, S100 calcium-binding protein B, and total tau were measured within 24 h from admission. The patients were divided into favorable (Glasgow Outcome Scale-Extended 5-8, n = 49) and unfavorable (Glasgow Outcome Scale-Extended 1-4, n = 33) groups. The outcome was assessed 6-12 months after injury. An optimal predictive panel was investigated with the sensitivity set at 90-100%. Results: The HCTS alone yielded a sensitivity of 97.0% (95% CI: 90.9-100) and specificity of 22.4% (95% CI: 10.2-32.7) and partial area under the curve of the receiver operating characteristic of 2.5% (95% CI: 1.1-4.7), in discriminating patients with favorable and unfavorable outcomes. The threshold to detect a patient with unfavorable outcome was an HCTS > 1. The three best individually performing biomarkers in outcome prediction were Aß40, Aß42, and neurofilament light. The optimal panel included IL-10, Aß40, and the HCTS reaching a partial area under the curve of the receiver operating characteristic of 3.4% (95% CI: 1.7-6.2) with a sensitivity of 90.9% (95% CI: 81.8-100) and specificity of 59.2% (95% CI: 40.8-69.4). Conclusion: Admission plasma levels of IL-10 and Aß40 significantly improve the prognostication ability of the HCTS after TBI.

Alterations in Microstructure and Local Fiber Orientation of White Matter Are Associated with Outcome after Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) can have long-lasting consequences. We investigated white matter (WM) alterations at 6-12 months following mTBI using diffusion tensor imaging (DTI) and assessed if the alterations associate with outcome. Eighty-five patients with mTBI underwent diffusion-weighted magnetic resonance imaging (MRI) on average 8 months post-injury and patients' outcome was assessed at the time of imaging using the Glasgow Outcome Scale-Extended (GOS-E). Additionally, 30 age-matched patients with extracranial orthopedic injuries were used as control subjects. Voxel-wise analysis of the data was performed using a tract-based spatial statistics (TBSS) approach and differences in microstructural metrics between groups were investigated. Further, the susceptibility of the abnormalities to specific fiber orientations was investigated by analyzing the first eigenvector of the diffusion tensor in the voxels with significant differences. We found significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) and radial diffusivity (RD) in patients with mTBI compared with control subjects, whereas no significant differences were observed in axial diffusivity (AD) between the groups. The differences were present bilaterally in several WM regions and correlated with outcome. Moreover, multiple clusters were found in the principal fiber orientations of the significant voxels in anisotropy, and similar orientation patterns were found for the diffusivity metrics. These directional clusters correlated with patients' functional outcome. Our study showed that mTBI is associated with WM changes at the chronic stage and these alterations occur in several WM regions. In addition, several significant clusters of WM alterations in specific fiber orientations were found and these clusters were associated with outcome.

Admission Levels of Total Tau and ß-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 ß-amyloid isoforms 1-40 (Aß40) and 1-42 (Aß42) 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, Aß40, and Aß42. 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, Aß40, and Aß42 were not significantly different between patients with complete and incomplete recovery. The levels of T-tau, Aß40, and Aß42 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, Aß40, and Aß42 did not significantly differ between the outcome groups either within the CT-positive or CT-negative subgroups. Levels of Aß40 and Aß42 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, Aß40, and Aß42 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.

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 S100ß, 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 <24 h post trauma. The outcome was measured >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 S100ß and clinical parameters improves outcome prediction models in TBI.

Integrative Analysis of Circulating Metabolite Profiles and Magnetic Resonance Imaging Metrics in Patients with Traumatic Brain Injury.

Recent evidence suggests that patients with traumatic brain injuries (TBIs) have a distinct circulating metabolic profile. However, it is unclear if this metabolomic profile corresponds to changes in brain morphology as observed by magnetic resonance imaging (MRI). The aim of this study was to explore how circulating serum metabolites, following TBI, relate to structural MRI (sMRI) findings. Serum samples were collected upon admission to the emergency department from patients suffering from acute TBI and metabolites were measured using mass spectrometry-based metabolomics. Most of these patients sustained a mild TBI. In the same patients, sMRIs were taken and volumetric data were extracted (138 metrics). From a pool of 203 eligible screened patients, 96 met the inclusion criteria for this study. Metabolites were summarized as eight clusters and sMRI data were reduced to 15 independent components (ICs). Partial correlation analysis showed that four metabolite clusters had significant associations with specific ICs, reflecting both the grey and white matter brain injury. Multiple machine learning approaches were then applied in order to investigate if circulating metabolites could distinguish between positive and negative sMRI findings. A logistic regression model was developed, comprised of two metabolic predictors (erythronic acid and myo-inositol), which, together with neurofilament light polypeptide (NF-L), discriminated positive and negative sMRI findings with an area under the curve of the receiver-operating characteristic of 0.85 (specificity = 0.89, sensitivity = 0.65). The results of this study show that metabolomic analysis of blood samples upon admission, either alone or in combination with protein biomarkers, can provide valuable information about the impact of TBI on brain structural changes.

Machine learning-based dynamic mortality prediction after traumatic brain injury.

Our aim was to create simple and largely scalable machine learning-based algorithms that could predict mortality in a real-time fashion during intensive care after traumatic brain injury. We performed an observational multicenter study including adult TBI patients that were monitored for intracranial pressure (ICP) for at least 24 h in three ICUs. We used machine learning-based logistic regression modeling to create two algorithms (based on ICP, mean arterial pressure [MAP], cerebral perfusion pressure [CPP] and Glasgow Coma Scale [GCS]) to predict 30-day mortality. We used a stratified cross-validation technique for internal validation. Of 472 included patients, 92 patients (19%) died within 30 days. Following cross-validation, the ICP-MAP-CPP algorithm's area under the receiver operating characteristic curve (AUC) increased from 0.67 (95% confidence interval [CI] 0.60-0.74) on day 1 to 0.81 (95% CI 0.75-0.87) on day 5. The ICP-MAP-CPP-GCS algorithm's AUC increased from 0.72 (95% CI 0.64-0.78) on day 1 to 0.84 (95% CI 0.78-0.90) on day 5. Algorithm misclassification was seen among patients undergoing decompressive craniectomy. In conclusion, we present a new concept of dynamic prognostication for patients with TBI treated in the ICU. Our simple algorithms, based on only three and four main variables, discriminated between survivors and non-survivors with accuracies up to 81% and 84%. These open-sourced simple algorithms can likely be further developed, also in low and middle-income countries.

Correlation of Blood Biomarkers and Biomarker Panels with Traumatic Findings on Computed Tomography after Traumatic Brain Injury.

The aim of the study was to examine the ability of eight protein biomarkers and their combinations in discriminating computed tomography (CT)-negative and CT-positive patients with traumatic brain injury (TBI), utilizing highly sensitive immunoassays in a well-characterized cohort. Blood samples were obtained from 160 patients with acute TBI within 24 h of admission. Levels of ß-amyloid isoforms 1-40 (Aß40) and 1-42 (Aß42), glial fibrillary acidic protein (GFAP), heart fatty-acid binding protein (H-FABP), interleukin 10 (IL-10), neurofilament light (NF-L), S100 calcium-binding protein B (S100B), and tau were measured. Patients were divided into CT-negative (n = 65) and CT-positive (n = 95), and analyses were conducted separately for TBIs of all severities (Glasgow Coma Scale [GCS] score 3-15) and mild TBIs (mTBIs; GCS 13-15). NF-L, GFAP, and tau were the best in discriminating CT-negative and CT-positive patients, both in patients with mTBI and with all severities. In patients with all severities, area under the curve of the receiver operating characteristic (AUC) was 0.822, 0.817, and 0.781 for GFAP, NF-L, and tau, respectively. In patients with mTBI, AUC was 0.720, 0.689, and 0.676, for GFAP, tau, and NF-L, respectively. The best panel of three biomarkers for discriminating CT-negative and CT-positive patients in the group of all severities was a combination of GFAP+H-FABP+IL-10, with a sensitivity of 100% and specificity of 38.5%. In patients with mTBI, the best panel of three biomarkers was H-FABP+S100B+tau, with a sensitivity of 100% and specificity of 46.4%. Panels of biomarkers outperform individual biomarkers in separating CT-negative and CT-positive patients. Panels consisted mainly of different biomarkers than those that performed best as an individual biomarker.

Risk Factors for Recurrent Hematoma After Surgery for Acute Traumatic Subdural Hematoma.

OBJECTIVE: The development of postcraniotomy hematoma (PCH) after surgery for acute traumatic subdural hematoma (aSDH) has been associated with an increased risk of a poor outcome. The risk factors contributing to PCH remain poorly understood. Our aim was to study the potential risk factors for PCH in a consecutive series of surgically evacuated patients with aSDH. METHODS: A total of 132 patients with aSDH treated at Turku University Hospital (Turku, Finland) from 2008 to 2012 were enrolled in the present retrospective cohort study. The demographic, clinical, laboratory, and imaging data were collected from the medical records. A comprehensive analysis of the data using 6 different univariate methods, including machine learning and multivariate analyses, was conducted to identify the factors related to PCH. RESULTS: The incidence of PCH after primary surgery for traumatic aSDH was 10.6%. The patients experiencing PCH were younger (P = 0.04). No difference was found in the use of anticoagulant or antiplatelet medication for the patients with and without PCH. Multivariate analyses identified alcohol inebriation at the time of injury (odds ratio [OR], 12.67; P = 0.041) and hypocapnia (OR, 26.09; P = 0.003) as independent risk factors for PCH. The patients with PCH had had hyponatremia (OR, 0.08; P = 0.018) less often, and their maximal systolic blood pressure was lower (OR, 0.94; P = 0.009). The area under the curve for the multivariate model was 0.96 (P = 0.049), with a Youden index of 0.88. CONCLUSIONS: The results suggest that alcohol inebriation at the time of injury and hypocapnia during hospitalization are risk factors for the development of PCH.

Early Levels of Glial Fibrillary Acidic Protein and Neurofilament Light Protein in Predicting the Outcome of Mild Traumatic Brain Injury.

The purpose of this study was to correlate the early levels of glial fibrillary acidic protein (GFAP) and neurofilament light protein (NF-L) with outcome in patients with mild traumatic brain injury (mTBI). A total of 107 patients with mTBI (Glasgow Coma Scale ≥13) who had blood samples for GFAP and NF-L available within 24 h of arrival were included. Patients with mTBI were divided into computed tomography (CT)-positive and CT-negative groups. Glasgow Outcome Scale-Extended (GOSE) was used to assess the outcome. Outcomes were defined as complete (GOSE 8) versus incomplete (GOSE <8), and favorable (GOSE 5-8) versus unfavorable (GOSE 1-4). GFAP and NF-L concentrations in blood were measured using ultrasensitive single molecule array technology. Patients with incomplete recovery had significantly higher levels of NF-L compared with those with complete recovery (p = 0.005). The levels of GFAP and NF-L were significantly higher in patients with unfavorable outcome than in patients with favorable outcome (p = 0.002 for GFAP and p < 0.001 for NF-L). For predicting favorable outcome, the area under the receiver operating characteristic curve for GFAP and NF-L was 0.755 and 0.826, respectively. In a multi-variate logistic regression model, the level of NF-L was still a significant predictor for complete recovery (odds ratio [OR] = 1.008; 95% confidence interval [CI], 1.000-1.016). Moreover, the level of NF-L was a significant predictor for complete recovery in CT-positive patients (OR = 1.009; 95% CI, 1.001-1.016). The early levels of GFAP and NF-L are significantly correlated with the outcome in patients with mTBI. The level of NF-L within 24 h from arrival has a significant predictive value in mTBI also in a multi-variate model.

Serum Metabolites Associated with Computed Tomography Findings after Traumatic Brain Injury.

There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish among different types of injuries observed. Logistical regression models using metabolite data from the discovery cohort (n = 144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and those with negative findings on head CT. The resultant models were then tested in the validation cohort (n = 66, Cambridge, United Kingdom). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (area under the curve [AUC] = 0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives, and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC = 0.77 in Turku patients and AUC = 0.73 in Cambridge patients). Further, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC = 0.87 in Turku patients and AUC = 0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.