Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study.

Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. We studied the chronic effect of COVID-19 on cerebrovascular health, in relation to acute severity, adverse clinical outcomes and in contrast to control group data. Here we assess cerebrovascular health in 45 patients six months after hospitalisation for acute COVID-19 using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Acute COVID-19 severity was indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. Chronic widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. The level of cerebrovascular dysfunction was associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

Validation of cross-sectional and longitudinal ComBat harmonization methods for magnetic resonance imaging data on a travelling subject cohort.

Background: The growth in multi-center neuroimaging studies generated a need for methods that mitigate the differences in hardware and acquisition protocols across sites i.e., scanner effects. ComBat harmonization methods have shown promise but have not yet been tested on all the data types commonly studied with magnetic resonance imaging (MRI). This study aimed to validate neuroCombat, longCombat and gamCombat on both structural and diffusion metrics in both cross-sectional and longitudinal data. Methods: We used a travelling subject design whereby 73 healthy volunteers contributed 161 scans across two sites and four machines using one T1 and five diffusion MRI protocols. Scanner was defined as a composite of site, machine and protocol. A common pipeline extracted two structural metrics (volumes and cortical thickness) and two diffusion tensor imaging metrics (mean diffusivity and fractional anisotropy) for seven regions of interest including gray and (except for cortical thickness) white matter regions. Results: Structural data exhibited no significant scanner effect and therefore did not benefit from harmonization in our particular cohort. Indeed, attempting harmonization obscured the true biological effect for some regions of interest. Diffusion data contained marked scanner effects and was successfully harmonized by all methods, resulting in smaller scanner effects and better detection of true biological effects. LongCombat less effectively reduced the scanner effect for cross-sectional white matter data but had a slightly lower probability of incorrectly finding group differences in simulations, compared to neuroCombat and gamCombat. False positive rates for all methods and all metrics did not significantly exceed 5%. Conclusions: Statistical harmonization of structural data is not always necessary and harmonization in the absence of a scanner effect may be harmful. Harmonization of diffusion MRI data is highly recommended with neuroCombat, longCombat and gamCombat performing well in cross-sectional and longitudinal settings.

Comparison of health-related quality of life in patients with traumatic brain injury, subarachnoid haemorrhage and cervical spine disease.

PURPOSE: The degree of disability that is acceptable to patients following traumatic brain injury (TBI) continues to be debated. While the dichotomization of outcome on the Glasgow Outcome Score (GOSE) into 'favourable' and 'unfavourable' continues to guide clinical decisions, this may not reflect an individual's subjective experience. The aim of this study is to assess how patients' self-reported quality of life (QoL) relates to objective outcome assessments and how it compares to other debilitating neurosurgical pathologies, including subarachnoid haemorrhage (SAH) and cervical myelopathy. METHOD: A retrospective analysis of over 1300 patients seen in Addenbrooke's Hospital, Cambridge, UK with TBI, SAH and patients pre- and post- cervical surgery was performed. QoL was assessed using the SF-36 questionnaire. Kruskal-Wallis test was used to analyse the difference in SF-36 domain scores between the four unpaired patient groups. To determine how the point of dichotomization of GOSE into 'favourable' and 'unfavourable' outcome affected QOL, SF-36 scores were compared between GOSE and mRS. RESULTS: There was a statistically significant difference in the median Physical Component Score (PCS) and Mental Component Score (MCS) of SF-36 between the three neurosurgical pathologies. Patients with TBI and SAH scored higher on most SF-36 domains when compared with cervical myelopathy patients in the severe category. While patients with Upper Severe Disability on GOSE showed significantly higher PC and MC scores compared to GOSE 3, there was a significant degree of variability in individual responses across the groups. CONCLUSION: A significant number of patients following TBI and SAH have better self-reported QOL than cervical spine patients and patients' subjective perception and expectations following injury do not always correspond to objective disability. These results can guide discussion of treatment and outcomes with patients and families.

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort.

Background: Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods: 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings: COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=​​0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance. Interpretation: Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed. Funding: This work was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC), NIHR Cambridge Clinical Research Facility (BRC-1215-20014), the Addenbrooke's Charities Trust and NIHR COVID-19 BioResource RG9402. AH is funded by the UK Dementia Research Institute Care Research and Technology Centre and Imperial College London Biomedical Research Centre. ETB and DKM are supported by NIHR Senior Investigator awards. JBR is supported by the Wellcome Trust (220258) and Medical Research Council (SUAG/051 G101400). VFJN is funded by an Academy of Medical Sciences/ The Health Foundation Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Development of the support needs after ICU (SNAC) questionnaire.

AIMS: To develop a questionnaire to identify Intensive Care survivor needs at key transitions during the recovery process, and assess its validity and reliability in a group of ICU survivors. METHODS: Development of the Support Needs After ICU (SNAC) questionnaire was based on a systematic scoping review, and analysis of patient interviews (n = 22). Face and content validity were assessed by service users (n = 12) and an expert panel of healthcare professionals (n = 6). A pilot survey among 200 ICU survivors assessed recruitment at one of five different stages after ICU discharge [(1) in hospital, (2) < 6 weeks, (3) 7 weeks to 6 months, (4) 7 to 12 months, or (5) 12 to 24 months post-hospital discharge]; to assess reliability of the SNAC questionnaire; and to conduct exploratory data analysis. Reliability was determined using Cronbach's alpha for internal consistency; intraclass correlation coefficients for test-retest reliability. We explored correlations with sociodemographic variables using Pearson's correlation coefficient; differences between questionnaire scores and patient demographics using one-way ANOVA. RESULTS: The SNAC questionnaire consisted of 32 items that assessed five categories of support needs (informational, emotional, instrumental [e.g. practical physical help, provision of equipment or training], appraisal [e.g. clinician feedback on recovery] and spiritual needs). ICU survivors were recruited from Northern Ireland, England and Scotland. From a total of 375 questionnaires distributed, 202 (54%) were returned. The questionnaire had high internal consistency (0.97) and high test-retest reliability (r = 0.8) with subcategories ranging from 0.3 to 0.9. CONCLUSIONS: The SNAC questionnaire appears to be a comprehensive, valid, and reliable questionnaire. Further research will enable more robust examination of its properties e.g. factor analysis, and establish its utility in identifying whether patients' support needs evolve over time. RELEVANCE TO CLINICAL PRACTICE: The SNAC questionnaire has the potential to be used to identify ICU survivors' needs and inform post-hospital support services.

Metabolic derangements are associated with impaired glucose delivery following traumatic brain injury.

Metabolic derangements following traumatic brain injury are poorly characterized. In this single-centre observational cohort study we combined 18F-FDG and multi-tracer oxygen-15 PET to comprehensively characterize the extent and spatial pattern of metabolic derangements. Twenty-six patients requiring sedation and ventilation with intracranial pressure monitoring following head injury within a Neurosciences Critical Care Unit, and 47 healthy volunteers were recruited. Eighteen volunteers were excluded for age over 60 years (n = 11), movement-related artefact (n = 3) or physiological instability during imaging (n = 4). We measured cerebral blood flow, blood volume, oxygen extraction fraction, and 18F-FDG transport into the brain (K1) and its phosphorylation (k3). We calculated oxygen metabolism, 18F-FDG influx rate constant (Ki), glucose metabolism and the oxygen/glucose metabolic ratio. Lesion core, penumbra and peri-penumbra, and normal-appearing brain, ischaemic brain volume and k3 hotspot regions were compared with plasma and microdialysis glucose in patients. Twenty-six head injury patients, median age 40 years (22 male, four female) underwent 34 combined 18F-FDG and oxygen-15 PET at early, intermediate, and late time points (within 24 h, Days 2-5, and Days 6-12 post-injury; n = 12, 8, and 14, respectively), and were compared with 20 volunteers, median age 43 years (15 male, five female) who underwent oxygen-15, and nine volunteers, median age 56 years (three male, six female) who underwent 18F-FDG PET. Higher plasma glucose was associated with higher microdialysate glucose. Blood flow and K1 were decreased in the vicinity of lesions, and closely related when blood flow was <25 ml/100 ml/min. Within normal-appearing brain, K1 was maintained despite lower blood flow than volunteers. Glucose utilization was globally reduced in comparison with volunteers (P < 0.001). k3 was variable; highest within lesions with some patients showing increases with blood flow <25 ml/100 ml/min, but falling steeply with blood flow lower than 12 ml/100 ml/min. k3 hotspots were found distant from lesions, with k3 increases associated with lower plasma glucose (Rho -0.33, P < 0.001) and microdialysis glucose (Rho -0.73, P = 0.02). k3 hotspots showed similar K1 and glucose metabolism to volunteers despite lower blood flow and oxygen metabolism (P < 0.001, both comparisons); oxygen extraction fraction increases consistent with ischaemia were uncommon. We show that glucose delivery was dependent on plasma glucose and cerebral blood flow. Overall glucose utilization was low, but regional increases were associated with reductions in glucose availability, blood flow and oxygen metabolism in the absence of ischaemia. Clinical management should optimize blood flow and glucose delivery and could explore the use of alternative energy substrates.

Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury.

Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.

Mild traumatic brain injury recovery: a growth curve modelling analysis over 2 years.

BACKGROUND: An improved understanding of the trajectory of recovery after mild traumatic brain injury is important to be able to understand individual patient outcomes, for longitudinal patient care and to aid the design of clinical trials. OBJECTIVE: To explore changes in health, well-being and cognition over the 2 years following mTBI using latent growth curve (LGC) modelling. METHODS: Sixty-one adults with mTBI presenting to a UK Major Trauma Centre completed comprehensive longitudinal assessment at up to five time points after injury: 2 weeks, 3 months, 6 months, 1 year and 2 years. RESULTS: Persisting problems were seen with neurological symptoms, cognitive issues and poor quality of life measures including 28% reporting incomplete recovery on the Glasgow Outcome Score Extended at 2 years. Harmful drinking, depression, psychological distress, disability, episodic memory and working memory did not improve significantly over the 2 years following injury. For other measures, including the Rivermead Post-Concussion Symptoms and Quality of Life after Brain Injury (QOLIBRI), LGC analysis revealed significant improvement over time with recovery tending to plateau at 3-6 months. INTERPRETATION: Significant impairment may persist as late as 2 years after mTBI despite some recovery over time. Longitudinal analyses which make use of all available data indicate that recovery from mTBI occurs over a longer timescale than is commonly believed. These findings point to the need for long-term management of mTBI targeting individuals with persisting impairment.

Influence of Concomitant Extracranial Injury on Functional and Cognitive Recovery From Mild Versus Moderateto Severe Traumatic Brain Injury.

OBJECTIVE: To determine the effect of extracranial injury (ECI) on 6-month outcome in patients with mild traumatic brain injury (TBI) versus moderate-to-severe TBI. PARTICIPANTS/SETTING: Patients with TBI (n = 135) or isolated orthopedic injury (n = 25) admitted to a UK major trauma center and healthy volunteers (n = 99). DESIGN: Case-control observational study. MAIN MEASURES: Primary outcomes: (a) Glasgow Outcome Scale Extended (GOSE), (b) depression, (c) quality of life (QOL), and (d) cognitive impairment including verbal fluency, episodic memory, short-term recognition memory, working memory, sustained attention, and attentional flexibility. RESULTS: Outcome was influenced by both TBI severity and concomitant ECI. The influence of ECI was restricted to mild TBI; GOSE, QOL, and depression outcomes were significantly poorer following moderate-to-severe TBI than after isolated mild TBI (but not relative to mild TBI plus ECI). Cognitive impairment was driven solely by TBI severity. General health, bodily pain, semantic verbal fluency, spatial recognition memory, working memory span, and attentional flexibility were unaffected by TBI severity and additional ECI. CONCLUSION: The presence of concomitant ECI ought to be considered alongside brain injury severity when characterizing the functional and neurocognitive effects of TBI, with each presenting challenges to recovery.

Accelerometery as a measure of modifiable physical activity in high-risk elderly preoperative patients: a prospective observational pilot study.

OBJECTIVES: To use wrist-worn accelerometers (Axivity AX3) to establish normative physical activity (PA) and acceptability data for the high-risk elderly preoperative population, to assess whether PA could be modified by a prehabilitation intervention as part of routine care, to assess any correlation between accelerometer-measured PA and self-reported PA and to assess the acceptability of wearing wrist-worn accelerometers in this population. STUDY DESIGN: Prospective, observational, pilot study. SETTING: Single National Health Service Hospital. PARTICIPANTS: Frail patients≥65 years awaiting major surgery referred to a multidisciplinary preoperative clinic at which they received a routine intervention aimed at improving their PA. 35 patients were recruited. Average age 79.9 years (SD=5.6). PRIMARY OUTCOMES: Normative PA data measured as a mean daily Euclidean norm minus one (ENMO) in milli-gravitational units (mg). SECONDARY OUTCOMES: Measure PA levels (mg) following a routine preoperative intervention. Determine correlation between patient-reported PA (measured using the Physical Activity Scale for the Elderly) and accelerometer-measured PA (mg). Assess acceptability of wearing a wrist-worn accelerometer measured using Visual Analogue Scale (VAS) questionnaire and device wear time (hours). RESULTS: Median baseline daily PA was 14.3 mg (IQR 9.75-22.04) with an improvement in PA detected following the intervention (median ENMO post intervention 20.91 mg (IQR 14.83-27.53), p=0.022). There was no significant correlation between accelerometer-measured and self-reported PA (baseline ρ=0.162 (p=0.4), post intervention ρ=-0.144 (p=0.5)). We found high acceptability ratings (median score of 10/10 on VAS, IQR 8-10) and wear-time compliance (163.2 hours (IQR 150-167.5) preintervention and 166.1 hours (IQR 162.5-167) post intervention). CONCLUSIONS: Accelerometery is acceptable to this population and increases in PA levels measured following an unoptimised routine clinical intervention which indicates that health behavioural change interventions may be successful during the preoperative period. Accelerometers may therefore be a useful tool to design and validate interventions for improving PA in this setting. TRIAL REGISTRATION NUMBER: NCT03737903.

Feasibility of individualised severe traumatic brain injury management using an automated assessment of optimal cerebral perfusion pressure: the COGiTATE phase II study protocol.

INTRODUCTION: Individualising therapy is an important challenge for intensive care of patients with severe traumatic brain injury (TBI). Targeting a cerebral perfusion pressure (CPP) tailored to optimise cerebrovascular autoregulation has been suggested as an attractive strategy on the basis of a large body of retrospective observational data. The objective of this study is to prospectively assess the feasibility and safety of such a strategy compared with fixed thresholds which is the current standard of care from international consensus guidelines. METHODS AND ANALYSIS: CPPOpt Guided Therapy: Assessment of Target Effectiveness (COGiTATE) is a prospective, multicentre, non-blinded randomised, controlled trial coordinated from Maastricht University Medical Center, Maastricht (The Netherlands). The other original participating centres are Cambridge University NHS Foundation Trust, Cambridge (UK), and University Hospitals Leuven, Leuven (Belgium). Adult severe TBI patients requiring intracranial pressure monitoring are randomised within the first 24 hours of admission in neurocritical care unit. For the control arm, the CPP target is the Brain Trauma Foundation guidelines target (60-70 mm Hg); for the intervention group an automated CPP target is provided as the CPP at which the patient's cerebrovascular reactivity is best preserved (CPPopt). For a maximum of 5 days, attending clinicians review the CPP target 4-hourly. The main hypothesis of COGiTATE are: (1) in the intervention group the percentage of the monitored time with measured CPP within a range of 5 mm Hg above or below CPPopt will reach 36%; (2) the difference in between groups in daily therapy intensity level score will be lower or equal to 3. ETHICS AND DISSEMINATION: Ethical approval has been obtained for each participating centre. The results will be presented at international scientific conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02982122.

Neurocognitive testing in the emergency department: A potential assessment tool for mild traumatic brain injury.

OBJECTIVE: Despite mild traumatic brain injury (mTBI) accounting for 80% of head injury diagnoses, recognition of individuals at risk of cognitive dysfunction remains a challenge in the acute setting. The objective of this study was to evaluate the feasibility and potential role for computerised cognitive testing as part of a complete ED head injury assessment. METHODS: mTBI patients (n = 36) who incurred a head injury within 24 h of presentation to the ED were compared to trauma controls (n = 20) and healthy controls (n = 20) on tests assessing reaction time, speed and attention, episodic memory, working memory and executive functioning. Testing occurred during their visit to the ED at a mean of 12 h post-injury for mTBI and 9.4 h for trauma controls. These tasks were part of the Cambridge Neuropsychological Test Automated Battery iPad application. Healthy controls were tested in both a quiet environment and the ED to investigate the potential effects of noise and distraction on neurocognitive function. RESULTS: Reaction time was significantly slower in the mTBI group compared to trauma patients (P = 0.015) and healthy controls (P = 0.011), and deficits were also seen in working memory compared to healthy controls (P ≤ 0.001) and in executive functioning (P = 0.021 and P < 0.001) compared to trauma and healthy controls. Performances in the control group did not differ between testing environments. CONCLUSION: Computerised neurocognitive testing in the ED is feasible and can be utilised to detect deficits in cognitive performance in the mTBI population as part of a routine head injury assessment.

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.

Spectrum of outcomes following traumatic brain injury-relationship between functional impairment and health-related quality of life.

BACKGROUND: The outcome following traumatic brain injury (TBI) is heterogeneous and poorly defined and physical disability scales like the extended Glasgow Outcome Score (GOSE) while providing valuation information in terms of broad categorisation of outcome are unlikely to capture the full spectrum of deficits. Quality of life questionnaires such as SF-36 are emerging as potential tools to help characterise factors important to patients' recovery. This study assessed the association between physical disability and subjective health rating. The relationship is of value as it may help evaluate the impact of TBI on patients' lives and facilitate the delivery of appropriate neuro-rehabilitation services. METHODS: A single-centre retrospective study was undertaken to assess the relationship between physical outcome as measured by GOSE and quality of life captured by the SF-36 questionnaire. Cronbach's alpha was calculated for each of the eight SF-36 domains to measure internal consistency of the test. Multivariate analysis of variance was conducted to look at the association between GOSE and the physical (PCS) and mental (MCS) component scores on the SF-36. Finally, we performed a generalised linear mixed model (GLMM) to assess the relative contribution of GOSE score, age at the time of trauma, sex and TBI duration towards MCS and PCS rating. RESULTS: There is a statistically significant difference in the MCS and PCS scores based on patients' GOSE scores. The mean scores of the eight SF-36 domains showed significant association with GOSE. GLMM demonstrated that GOSE was the strongest predictor of PCS and MCS. Age was an important variable in the PCS score while time following trauma was a significant predictor of MCS rating. CONCLUSIONS: This study highlights that patients' physical outcome following TBI is a strong predictor of the subjective mental and physical health. Nevertheless, there remains tremendous variability in individual SF-36 scores for each GOSE category, highlighting that additional factors play a role in determining quality of life.

Normobaric hyperoxia does not improve derangements in diffusion tensor imaging found distant from visible contusions following acute traumatic brain injury.

We have previously shown that normobaric hyperoxia may benefit peri-lesional brain and white matter following traumatic brain injury (TBI). This study examined the impact of brief exposure to hyperoxia using diffusion tensor imaging (DTI) to identify axonal injury distant from contusions. Fourteen patients with acute moderate/severe TBI underwent baseline DTI and following one hour of 80% oxygen. Thirty-two controls underwent DTI, with 6 undergoing imaging following graded exposure to oxygen. Visible lesions were excluded and data compared with controls. We used the 99% prediction interval (PI) for zero change from historical control reproducibility measurements to demonstrate significant change following hyperoxia. Following hyperoxia DTI was unchanged in controls. In patients following hyperoxia, mean diffusivity (MD) was unchanged despite baseline values lower than controls (p < 0.05), and fractional anisotropy (FA) was lower within the left uncinate fasciculus, right caudate and occipital regions (p < 0.05). 16% of white and 14% of mixed cortical and grey matter patient regions showed FA decreases greater than the 99% PI for zero change. The mechanistic basis for some findings are unclear, but suggest that a short period of normobaric hyperoxia is not beneficial in this context. Confirmation following a longer period of hyperoxia is required.

Neural correlates of visual memory in patients with diffuse axonal injury.

PRIMARY OBJECTIVE: To investigate the neural substrates of visual memory in a sample of patients with traumatic brain injury (TBI). We hypothesized that patients with decreased grey and white matter volume in frontal and parietal cortices as well as medial temporal and occipital lobes would perform poorly on the tests of visual memory analysed. METHODS AND PROCEDURES: 39 patients and 53 controls were assessed on tests of visual memory and learning from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Patients with TBI were scanned with magnetic resonance imaging (MRI). Partial correlations and multiple regression analyses were used to examine relationships between cognitive variables and MRI volumetric findings. This study complements and extends previous studies by performing volumetric comparisons on a variety of resolution levels, from whole brain to voxel-based level analysis. MAIN OUTCOMES AND RESULTS: Patients with TBI performed significantly worse than controls in all the tasks assessed. Performance was associated with wide-spread reductions in grey and white matter volume of several cortical and subcortical structures as well as with cerebrospinal fluid space enlargement in accordance with previous studies of memory in patients with TBI and cognitive models suggesting that memory problems involve the alteration of multiple systems. CONCLUSIONS: Our results propose that compromised visual memory in patients with TBI is related to a distributed pattern of volume loss in regions mediating memory and attentional processing.

Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 Are Not Specific Biomarkers for Mild CT-Negative Traumatic Brain Injury.

Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) have been studied as potential biomarkers of mild traumatic brain injury (mTBI). We report the levels of GFAP and UCH-L1 in patients with acute orthopedic injuries without central nervous system involvement, and relate them to the type of extracranial injury, head magnetic resonance imaging (MRI) findings, and levels of GFAP and UCH-L1 in patients with CT-negative mTBI. Serum UCH-L1 and GFAP were longitudinally measured from 73 patients with acute orthopedic injury on arrival and on days 1, 2, 3, 7 after admission, and on the follow-up visit 3-10 months after the injury. The injury types were recorded, and 71% patients underwent also head MRI. The results were compared with those found in patients with CT-negative mTBI (n = 93). The levels of GFAP were higher in patients with acute orthopedic trauma than in patients with CT-negative mTBI (p = 0.026) on arrival; however, no differences were found on the following days. The levels of UCH-L1 were not significantly different between these two groups at any measured point of time. Levels of GFAP and UCH-L1 were not able to distinguish patients with CT-negative mTBI from patients with orthopedic trauma. Patients with orthopedic trauma and high levels of UCH-L1 or GFAP values may be falsely diagnosed as having a concomitant mTBI, predisposing them to unwarranted diagnostics and unnecessary brain imaging. This casts a significant doubt on the diagnostic value of GFAP and UCH-L1 in cases with mTBI.

Pathophysiologic Mechanisms of Cerebral Ischemia and Diffusion Hypoxia in Traumatic Brain Injury.

IMPORTANCE: Combined oxygen 15-labeled positron emission tomography (15O PET) and brain tissue oximetry have demonstrated increased oxygen diffusion gradients in hypoxic regions after traumatic brain injury (TBI). These data are consistent with microvascular ischemia and are supported by pathologic studies showing widespread microvascular collapse, perivascular edema, and microthrombosis associated with selective neuronal loss. Fluorine 18-labeled fluoromisonidazole ([18F]FMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings. OBJECTIVE: To combine [18F]FMISO and 15O PET to demonstrate the relative burden, distribution, and physiologic signatures of conventional macrovascular and microvascular ischemia in early TBI. DESIGN, SETTING, AND PARTICIPANTS: This case-control study included 10 patients who underwent [18F]FMISO and 15O PET within 1 to 8 days of severe or moderate TBI. Two cohorts of 10 healthy volunteers underwent [18F]FMISO or 15O PET. The study was performed at the Wolfson Brain Imaging Centre of Addenbrooke's Hospital. Cerebral blood flow, cerebral blood volume, cerebral oxygen metabolism (CMRO2), oxygen extraction fraction, and brain tissue oximetry were measured in patients during [18F]FMISO and 15O PET imaging. Similar data were obtained from control cohorts. Data were collected from November 23, 2007, to May 22, 2012, and analyzed from December 3, 2012, to January 6, 2016. MAIN OUTCOMES AND MEASURES: Estimated ischemic brain volume (IBV) and hypoxic brain volume (HBV) and a comparison of their spatial distribution and physiologic signatures. RESULTS: The 10 patients with TBI (9 men and 1 woman) had a median age of 59 (range, 30-68) years; the 2 control cohorts (8 men and 2 women each) had median ages of 53 (range, 41-76) and 45 (range, 29-59) years. Compared with controls, patients with TBI had a higher median IBV (56 [range, 9-281] vs 1 [range, 0-11] mL; P < .001) and a higher median HBV (29 [range, 0-106] vs 9 [range, 1-24] mL; P = .02). Although both pathophysiologic tissue classes were present within injured and normal appearing brains, their spatial distributions were poorly matched. When compared with tissue within the IBV compartment, the HBV compartment showed similar median cerebral blood flow (17 [range, 11-40] vs 14 [range, 6-22] mL/100 mL/min), cerebral blood volume (2.4 [range, 1.6- 4.2] vs 3.9 [range, 3.4-4.8] mL/100 mL), and CMRO2 (44 [range, 27-67] vs 71 [range, 34-88] µmol/100 mL/min) but a lower oxygen extraction fraction (38% [range, 29%-50%] vs 89% [range, 75%-100%]; P < .001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with brain tissue oximetry monitoring suggested that the threshold for increased [18F]FMISO trapping is probably 15 mm Hg or lower. CONCLUSIONS AND RELEVANCE: Tissue hypoxia after TBI is not confined to regions with structural abnormality and can occur in the absence of conventional macrovascular ischemia. This physiologic signature is consistent with microvascular ischemia and is a target for novel neuroprotective strategies.

The Levels of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 During the First Week After a Traumatic Brain Injury: Correlations With Clinical and Imaging Findings.

BACKGROUND: Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) are promising biomarkers of traumatic brain injury (TBI). OBJECTIVE: We investigated the relation of the GFAP and UCH-L1 levels to the severity of TBI during the first week after injury. METHODS: Plasma UCH-L1 and GFAP were measured from 324 consecutive patients with acute TBI and 81 control subject enrolled in a 2-center prospective study. The baseline measures included initial Glasgow Coma Scale (GCS), head computed tomographic (CT) scan at admission, and blood samples for protein biomarkers that were collected at admission and on days 1, 2, 3, and 7 after injury. RESULTS: Plasma levels of GFAP and UCH-L1 during the first 2 days after the injury strongly correlated with the initial severity of TBI as assessed with GCS. Additionally, levels of UCH-L1 on the seventh day after the injury were significantly related to the admission GCS scores. At admission, both biomarkers were capable of distinguishing mass lesions from diffuse injuries in CT, and the area under the curve of the receiver-operating characteristic curve for prediction of any pathological finding in CT was 0.739 (95% confidence interval, 0.636-0.815) and 0.621 (95% confidence interval, 0.517-0.713) for GFAP and UCH-L1, respectively. CONCLUSION: These results support the prior findings of the potential role of GFAP and UCH-L1 in acute-phase diagnostics of TBI. The novel finding is that levels of GFAP and UCH-L1 correlated with the initial severity of TBI during the first 2 days after the injury, thus enabling a window for TBI diagnostics with latency. ABBREVIATIONS: AUC, area under the curveCI, confidence intervalED, emergency departmentGCS, Glasgow Coma ScaleGRAP, glial fibrillary acidic proteinIMPACT, International Mission for Prognosis and Clinical TrialROC, receiver-operating characteristicTBI, traumatic brain injuryTRACK-TBI, Transforming Research and Clinical Knowledge in Traumatic Brain InjuryUCH-L1, ubiquitin C-terminal hydrolase-L1.