RESUMEN
BACKGROUND: Brain recovery mechanisms after injuries like aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI) involve brain plasticity, synaptic regeneration, and neuroinflammation. We hypothesized that serum levels of the p75 neurotrophic receptor (p75NTR) and associated signaling proteins, as well as differentially expressed (DE) microRNAs, could predict recovery outcomes irrespective of injury type. METHODS: A prospective patient cohort with ischemic stroke (IS, n = 30), aneurysmal subarachnoid hemorrhage (aSAH, n = 31), and traumatic brain injury (TBI, n = 13) were evaluated (total n = 74). Serum samples were collected at two post-injury intervals (early: 1-3 days, late: 4-8 days), and outcomes were assessed after three months using the modified Rankin Scale (mRS), categorizing outcomes as favorable (mRS 0-3) or unfavorable (mRS 4-6). Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1ß, TNFα, and cyclophilin. DE microRNAs were identified using DESeq2, and their target genes were predicted. Serum molecules between patients with differing outcomes were compared using a Kolmogorov-Smirnov test, 2-tailed t-test and multivariate linear discriminant analysis (LDA). RESULTS: Favorable (n = 46) and unfavorable (n = 28) outcome cohorts were balanced with age and sex (p = 0.25 and 0.63). None of the studied proteins correlated with age. Combinatory LDA of the six protein biomarkers indicated strong prognostic value for favorable outcomes (OR 2.09; AUC = 70.3%, p = 0.0058). MicroRNA expression changes over time were identified in the aSAH, TBI, and IS groups (p < 0.05, FDR corrected). Twenty-three microRNAs were commonly DE across all brain injury groups when comparing favorable and unfavorable outcomes (p < 0.05). LDA of four microRNAs targeting the studied proteins showed high prognostic accuracy (OR 11.7; AUC = 94.1%, p = 0.016). CONCLUSIONS: The combined prognostic microRNA and protein biomarker models demonstrated accurate outcome prognostication across diverse injury types, implying the presence of a common recovery mechanism. DE microRNAs were found to target the studied molecules, suggesting a potential mechanistic role in recovery. Further investigation is warranted to study these molecules in prognostication, as well as therapeutic targets for enhancing recovery.
RESUMEN
AIMS AND SCOPE: The aim of this panel was to develop consensus recommendations on targeted temperature control (TTC) in patients with severe traumatic brain injury (TBI) and in patients with moderate TBI who deteriorate and require admission to the intensive care unit for intracranial pressure (ICP) management. METHODS: A group of 18 international neuro-intensive care experts in the acute management of TBI participated in a modified Delphi process. An online anonymised survey based on a systematic literature review was completed ahead of the meeting, before the group convened to explore the level of consensus on TTC following TBI. Outputs from the meeting were combined into a further anonymous online survey round to finalise recommendations. Thresholds of ≥ 16 out of 18 panel members in agreement (≥ 88%) for strong consensus and ≥ 14 out of 18 (≥ 78%) for moderate consensus were prospectively set for all statements. RESULTS: Strong consensus was reached on TTC being essential for high-quality TBI care. It was recommended that temperature should be monitored continuously, and that fever should be promptly identified and managed in patients perceived to be at risk of secondary brain injury. Controlled normothermia (36.0-37.5 °C) was strongly recommended as a therapeutic option to be considered in tier 1 and 2 of the Seattle International Severe Traumatic Brain Injury Consensus Conference ICP management protocol. Temperature control targets should be individualised based on the perceived risk of secondary brain injury and fever aetiology. CONCLUSIONS: Based on a modified Delphi expert consensus process, this report aims to inform on best practices for TTC delivery for patients following TBI, and to highlight areas of need for further research to improve clinical guidelines in this setting.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Consenso , Técnica Delphi , Hipotermia Inducida , Humanos , Lesiones Traumáticas del Encéfalo/terapia , Lesiones Traumáticas del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/complicaciones , Hipotermia Inducida/métodos , Hipotermia Inducida/normas , Unidades de Cuidados Intensivos/organización & administración , Presión Intracraneal/fisiología , Encuestas y CuestionariosRESUMEN
Acute brain injuries (ABIs) pose a substantial global burden, demanding effective prognostic indicators for outcomes. This study explores the potential of urinary p75 neurotrophin receptor (p75NTR) concentration as a prognostic biomarker, particularly in relation to unfavorable outcomes. The study involved 46 ABI patients, comprising sub-cohorts of aneurysmal subarachnoid hemorrhage, ischemic stroke, and traumatic brain injury. Furthermore, we had four healthy controls. Samples were systematically collected from patients treated at the University Hospital of Turku between 2017 and 2019, at early (1.50 ± 0.70 days) and late (9.17 ± 3.40 days) post-admission time points. Urinary p75NTR levels, measured by ELISA and normalized to creatinine, were compared against patients' outcomes using the modified Rankin Scale (mRS). Early urine samples showed no significant p75NTR concentration difference between favorable and unfavorable mRS groups. In contrast, late samples exhibited a statistically significant increase in p75NTR concentrations in the unfavorable group (p = 0.033), demonstrating good prognostic accuracy (AUC = 70.9%, 95% CI = 53-89%, p = 0.03). Assessment of p75NTR concentration changes over time revealed no significant variation in the favorable group (p = 0.992) but a significant increase in the unfavorable group (p = 0.009). Moreover, p75NTR concentration was significantly higher in ABI patients (mean ± SD 40.49 ± 28.83-65.85 ± 35.04 ng/mg) compared to healthy controls (mean ± SD 0.54 ± 0.44 ng/mg), irrespective of sampling time or outcome (p < 0.0001). In conclusion, late urinary p75NTR concentrations emerged as a potential prognostic biomarker for ABIs, showing increased levels associated with unfavorable outcomes regardless of the specific type of brain injury. While early samples exhibited no significant differences, the observed late increases emphasize the time-dependent nature of this potential biomarker. Further validation in larger patient cohorts is crucial, highlighting the need for additional research to establish p75NTR as a reliable prognostic biomarker across various ABIs. Additionally, its potential role as a diagnostic biomarker warrants exploration.
RESUMEN
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.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Humanos , Estudios Prospectivos , Filamentos Intermedios , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Encefálicas/complicaciones , Escala de Consecuencias de GlasgowRESUMEN
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).
Asunto(s)
Lesiones Traumáticas del Encéfalo , Interleucina-10 , Humanos , Proteína 3 de Unión a Ácidos Grasos , Estudios Prospectivos , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Biomarcadores , Subunidad beta de la Proteína de Unión al Calcio S100 , Proteína Ácida Fibrilar de la GlíaRESUMEN
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.
RESUMEN
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.
Asunto(s)
Conmoción Encefálica , Lesiones Traumáticas del Encéfalo , Sustancia Blanca , Humanos , Conmoción Encefálica/diagnóstico por imagen , Imagen de Difusión Tensora/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Filamentos Intermedios , Encéfalo , Sustancia Blanca/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/diagnóstico por imagenRESUMEN
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.
RESUMEN
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.
Asunto(s)
Pérdida de Líquido Cefalorraquídeo , Drenaje , Humanos , Estudios Retrospectivos , Drenaje/métodos , Presión Intracraneal , Ventriculostomía/métodosRESUMEN
Subarachnoid hemorrhage (SAH) is a serious condition, and a myocardial injury or dysfunction could contribute to the outcome. We assessed the prevalence and prognostic impact of cardiac involvement in a cohort with SAH. This is a prospective observational multicenter study. We included 192 patients treated for non-traumatic subarachnoid hemorrhage. We performed ECG recordings, echocardiographic examinations, and blood sampling within 24 h of admission and on days 3 and 7 and at 90 days. The primary endpoint was the evidence of cardiac involvement at 90 days, and the secondary endpoint was to examine the prevalence of a myocardial injury or dysfunction. The median age was 54.5 (interquartile range [IQR] 48.0-64.0) years, 44.3% were male and the median World Federation of Neurological Surgeons (WFNS) score was 2 (IQR 1-4). At day 90, 22/125 patients (17.6%) had left ventricular ejection fractions ≤ 50%, and 2/121 patients (1.7%) had evidence of a diastolic dysfunction as defined by mitral peak E-wave velocity by peak e' velocity (E/e') > 14. There was no prognostic impact from echocardiographic evidence of cardiac complications on neurological outcomes. The overall prevalence of cardiac dysfunction was modest. We found no demographic or SAH-related factors associated with 90 days cardiac dysfunction.
Asunto(s)
Cardiomiopatías , Hemorragia Subaracnoidea , Humanos , Masculino , Persona de Mediana Edad , Femenino , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/epidemiología , Hemorragia Subaracnoidea/complicaciones , Prevalencia , Ecocardiografía , Volumen Sistólico , Cardiomiopatías/complicacionesRESUMEN
Intensive care for patients with traumatic brain injury (TBI) aims to optimize intracranial pressure (ICP) and cerebral perfusion pressure (CPP). The transformation of ICP and CPP time-series data into a dynamic prediction model could aid clinicians to make more data-driven treatment decisions. We retrained and externally validated a machine learning model to dynamically predict the risk of mortality in patients with TBI. Retraining was done in 686 patients with 62,000 h of data and validation was done in two international cohorts including 638 patients with 60,000 h of data. The area under the receiver operating characteristic curve increased with time to 0.79 and 0.73 and the precision recall curve increased with time to 0.57 and 0.64 in the Swedish and American validation cohorts, respectively. The rate of false positives decreased to ≤2.5%. The algorithm provides dynamic mortality predictions during intensive care that improved with increasing data and may have a role as a clinical decision support tool.
RESUMEN
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.
RESUMEN
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 â¼8 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 â¼8 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 â¼8 months predicted white matter volume loss at >5 years, and annualized brain volume loss between â¼8 months and 5 years. Patients who worsened functionally between â¼8 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 â¼8 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.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Sustancia Blanca , Biomarcadores , Lesiones Encefálicas/complicaciones , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Imagen de Difusión Tensora/métodos , Progresión de la Enfermedad , Proteína Ácida Fibrilar de la Glía/metabolismo , HumanosRESUMEN
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.
Asunto(s)
Conmoción Encefálica , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Conmoción Encefálica/diagnóstico por imagen , Conmoción Encefálica/patología , Imagen de Difusión por Resonancia Magnética/métodos , Imagen de Difusión Tensora/métodos , Humanos , Imagen por Resonancia MagnéticaRESUMEN
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.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Proteína 3 de Unión a Ácidos Grasos , Interleucina-10 , Proteínas de Neurofilamentos , Subunidad beta de la Proteína de Unión al Calcio S100 , Adulto , Anciano , Biomarcadores , Lesiones Traumáticas del Encéfalo/diagnóstico , HumanosRESUMEN
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.
RESUMEN
P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR's related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n = 235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (p < 0.05, false discovery rate corrected). Gene network analyses showed multiple known and new targets in the p75NTR gene network. This study provides a comprehensive analysis and investigation into the current knowledge of p75NTR signaling networks and pathways. These results also identify several genes and their respective protein products as involved in the p75NTR network, which have not previously been clearly studied in this pathway. These results can be used to generate novel hypotheses to gain a greater understanding of p75NTR in acute brain injuries, neurodegenerative diseases and general response to cellular damage.
Asunto(s)
Algoritmos , Lesiones Encefálicas , Minería de Datos , Redes Reguladoras de Genes , Redes y Vías Metabólicas , Proteínas del Tejido Nervioso , Enfermedades Neurodegenerativas , Receptores de Factor de Crecimiento Nervioso , Transducción de Señal , Lesiones Encefálicas/genética , Lesiones Encefálicas/metabolismo , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , PubMed , Receptores de Factor de Crecimiento Nervioso/genética , Receptores de Factor de Crecimiento Nervioso/metabolismoRESUMEN
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.
RESUMEN
BACKGROUND: Cerebral autoregulation is often impaired after aneurysmal subarachnoid haemorrhage (aSAH). Dexmedetomidine is being increasingly used, but its effects on cerebral autoregulation in patients with aSAH have not been studied before. Dexmedetomidine could be a useful sedative in patients with aSAH as it enables neurological assessment during the infusion. The aim of this preliminary study was to compare the effects of dexmedetomidine on dynamic and static cerebral autoregulation with propofol and/or midazolam in patients with aSAH. METHODS: Ten patients were recruited. Dynamic and static cerebral autoregulation were assessed using transcranial Doppler ultrasound during propofol and/or midazolam infusion and then during three increasing doses of dexmedetomidine infusion (0.7, 1.0 and 1.4 µg/kg/h). Transient hyperaemic response ratio (THRR) and strength of autoregulation (SA) were calculated to assess dynamic cerebral autoregulation. Static rate of autoregulation (sRoR)% was calculated by using noradrenaline infusion to increase the mean arterial pressure 20 mm Hg above the baseline. RESULTS: Data from nine patients were analysed. Compared to baseline, we found no statistically significant changes in THRR or sROR%. THRR was (mean ± SD) 1.20 ± 0.14, 1.17 ± 0.13 (P = .93), 1.14 ± 0.09 (P = .72) and 1.19 ± 0.18 (P = 1.0) and sROR% was 150.89 ± 84.37, 75.22 ± 27.75 (P = .08), 128.25 ± 58.35 (P = .84) and 104.82 ± 36.92 (P = .42) at baseline and during 0.7, 1.0 and 1.4 µg/kg/h dexmedetomidine infusion, respectively. Dynamic SA was significantly reduced after 1.0 µg/kg/h dexmedetomidine (P = .02). CONCLUSIONS: Compared to propofol and/or midazolam, dexmedetomidine did not alter static cerebral autoregulation in aSAH patients, whereas a significant change was observed in dynamic SA. Further and larger studies with dexmedetomidine in aSAH patients are warranted.