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.

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.

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.

Injury profiles, demography and representativeness of patients with TBI attending a regional emergency department.

OBJECTIVES: The aim of this study was to describe the demography and epidemiology of Finnish patients with TBI and to analyse the representativeness of a study sample. MATERIALS AND METHODS: This prospective multi-centre study was conducted as part of an international collaboration within the EU-funded TBIcare project. The study group was recruited from patients attending the regional emergency department (ED) of the Turku University Hospital, Finland. Pre-defined exclusion criteria included age < 18 years, more than 2 weeks from the injury and uncertain diagnosis of TBI. To be included, a need for an acute head CT (NICE-criteria) was required. RESULTS: Of the 620 patients with TBI or suspected TBI, 203 patients were recruited to the study. Falls were the most common injury mechanism. The study group included more males than the total eligible population (p = 0.011), but no other statistical differences were found. The most common cause for being excluded was lack of information available to the research group before discharge (34%). CONCLUSION: This study supports previous findings that falls are the most common injury mechanism in the Western countries. Uncertainty about the diagnosis of TBI, lack of representativeness without continuous recruitment and poor information transfer about the ED attendees are major challenges for prospective TBI studies.

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.

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).

A comparison of diffusion tensor imaging tractography and constrained spherical deconvolution with automatic segmentation in traumatic brain injury.

Detection of microstructural white matter injury in traumatic brain injury (TBI) requires specialised imaging methods, of which diffusion tensor imaging (DTI) has been extensively studied. Newer fibre alignment estimation methods, such as constrained spherical deconvolution (CSD), are better than DTI in resolving crossing fibres that are ubiquitous in the brain and may improve the ability to detect microstructural injuries. Furthermore, automatic tract segmentation has the potential to improve tractography reliability and accelerate workflow compared to the manual segmentation commonly used. In this study, we compared the results of deterministic DTI based tractography and manual tract segmentation with CSD based probabilistic tractography and automatic tract segmentation using TractSeg. 37 participants with a history of TBI (with Glasgow Coma Scale 13-15) and persistent symptoms, and 41 healthy controls underwent deterministic DTI-based tractography with manual tract segmentation and probabilistic CSD-based tractography with TractSeg automatic segmentation.Fractional anisotropy (FA) and mean diffusivity of corpus callosum and three bilateral association tracts were measured. FA and MD values derived from both tractography methods were generally moderately to strongly correlated. CSD with TractSeg differentiated the groups based on FA, while DTI did not. CSD and TractSeg-based tractography may be more sensitive in detecting microstructural changes associated with TBI than deterministic DTI tractography. Additionally, CSD with TractSeg was found to be applicable at lower b-value and number of diffusion-encoding gradients data than previously reported.

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.

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.

Cerebral Microbleeds and Structural White Matter Integrity in Patients With Traumatic Brain Injury-A Diffusion Tensor Imaging Study.

Diffuse axonal injury (DAI) is a common neuropathological manifestation of traumatic brain injury (TBI), presenting as traumatic alterations in the cerebral white matter (WM) microstructure and often leading to long-term neurocognitive impairment. These WM alterations can be assessed using diffusion tensor imaging (DTI). Cerebral microbleeds (CMBs) are a common finding on head imaging in TBI and are often considered a visible sign of DAI, although they represent diffuse vascular injury. It is poorly known how they associate with long-term white matter integrity. This study included 20 patients with TBI and CMBs, 34 patients with TBI without CMBs, and 11 controls with orthopedic injuries. DTI was used to assess microstructural WM alterations. CMBs were detected using susceptibility-weighted imaging (SWI) and graded according to their location in the WM and total lesion load was counted. Patients underwent SWI within 2 months after injury. DTI and clinical outcome assessment were performed at an average of eight months after injury. Outcome was assessed using the extended Glasgow Outcome Scale (GOSe). The Glasgow Coma Scale (GCS) and length of post-traumatic amnesia (PTA) were used to assess clinical severity of the injury. We found that CMB grading and total lesion load were negatively associated with fractional anisotropy (FA) and positively associated with mean diffusivity (MD). Patients with TBI and CMBs had decreased FA and increased MD compared with patients with TBI without CMBs. CMBs were also associated with worse clinical outcome. When adjusting for the clinical severity of the injury, none of the mentioned associations were found. Thus, the difference in FA and MD is explained by patients with TBI and CMBs having more severe injuries. Our results suggest that CMBs are not associated with greater WM alterations when adjusting for the clinical severity of TBI. Thus, CMBs and WM alterations may not be strongly associated pathologies in TBI.

Volume Change in Frontal Cholinergic Structures After Traumatic Brain Injury and Cognitive Outcome.

The cholinergic nuclei in the basal forebrain innervate frontal cortical structures regulating attention. Our aim was to investigate if cognitive test results measuring attention relate to the longitudinal volume change of cholinergically innervated structures following traumatic brain injury (TBI). During the prospective, observational TBIcare project patients with all severities of TBI (n = 114) and controls with acute orthopedic injuries (n = 17) were recruited. Head MRI was obtained in both acute (mean 2 weeks post-injury) and late (mean 8 months) time points. T1-weighted 3D MR images were analyzed with an automatic segmentation method to evaluate longitudinal, structural brain volume change. The cognitive outcome was assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB). Analyses included 16 frontal cortical structures, of which four showed a significant correlation between post-traumatic volume change and the CANTAB test results. The strongest correlation was found between the volume loss of the supplementary motor cortex and motor screening task results (R-sq 0.16, p < 0.0001), where poorer test results correlated with greater atrophy. Of the measured sum structures, greater cortical gray matter atrophy rate showed a significant correlation with the poorer CANTAB test results. TBI caused volume loss of frontal cortical structures that are heavily innervated by cholinergic neurons is associated with neuropsychological test results measuring attention.

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.

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.

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.

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.

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.

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.

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.

Interaural intensity difference and ear advantage in listening to dichotic consonant-vowel syllable pairs.

The right-ear advantage (REA) is typically observed in verbal dichotic listening, indicating a left hemisphere superiority for speech processing. The REA could be thought of as a bottom-up, stimulus-driven laterality effect, caused by the preponderance of the contralateral neural fibers from the right ear to the auditory/speech processing areas in the left temporal lobe. The REA can, however, be modified by explicitly requiring the listeners to focus their attention alternatively on the left or right-ear stimuli, thus either countering or enhancing the bottom-up processes through top-down attentional control. In the present study, we manipulated the strength of the bottom-up REA by inducing an intensity difference between the right-ear and left-ear speech inputs in order to make the REA either weaker (left-ear input>right-ear input) or stronger (left-ear input

TMS-EEG reveals hemispheric asymmetries in top-down influences of posterior intraparietal cortex on behavior and visual event-related potentials.

Clinical data and behavioral studies using transcranial magnetic stimulation (TMS) suggest right-hemisphere dominance for top-down modulation of visual processing in humans. We used concurrent TMS-EEG to directly test for hemispheric differences in causal influences of the right and left intraparietal cortex on visual event-related potentials (ERPs). We stimulated the left and right posterior part of intraparietal sulcus (IPS1) while the participants were viewing and rating the visibility of bilaterally presented Gabor patches. Subjective visibility ratings showed that TMS of right IPS shifted the visibility toward the right hemifield, while TMS of left IPS did not have any behavioral effect. TMS of right IPS, but not left one, reduced the amplitude of posterior N1 potential, 180-220ms after stimulus-onset. The attenuation of N1 occurred bilaterally over the posterior areas of both hemispheres. Consistent with previous TMS-fMRI studies, this finding suggests that the right IPS has top-down control on the neural processing in visual cortex. As N1 most probably reflects reactivation of early visual areas, the current findings support the view that the posterior parietal cortex in the right hemisphere amplifies recurrent interactions in ventral visual areas during the time-window that is critical for conscious perception.