Use of diffusion tensor imaging to assess the impact of normobaric hyperoxia within at-risk pericontusional tissue after traumatic brain injury

Ischemia and metabolic dysfunction remain important causes of neuronal loss after head injury, and we have shown that normobaric hyperoxia may rescue such metabolic compromise. This study examines the impact of hyperoxia within injured brain using diffusion tensor imaging (DTI). Fourteen patients underwent DTI at baseline and after 1 hour of 80% oxygen. Using the apparent diffusion coefficient (ADC) we assessed the impact of hyperoxia within contusions and a 1 cm border zone of normal appearing pericontusion, and within a rim of perilesional reduced ADC consistent with cytotoxic edema and metabolic compromise. Seven healthy volunteers underwent imaging at 21%, 60%, and 100% oxygen. In volunteers there was no ADC change with hyperoxia, and contusion and pericontusion ADC values were higher than volunteers (P < 0.01). There was no ADC change after hyperoxia within contusion, but an increase within pericontusion (P < 0.05). We identified a rim of perilesional cytotoxic edema in 13 patients, and hyperoxia resulted in an ADC increase towards normal (P=0.02). We demonstrate that hyperoxia may result in benefit within the perilesional rim of cytotoxic edema. Future studies should address whether a longer period of hyperoxia has a favorable impact on the evolution of tissue injury

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.Dr. Veenith was supported by clinical research training fellowship from National institute of Academic Anaesthesia and Raymond Beverly Sackler studentship. VFJN is supported by a Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship. JPC was supported by Wellcome trust project grant. DKM is supported by an NIHR Senior Investigator Award. This work was supported by a Wellcome Trust Project Grant (WT093267) and Medical Research Council (UK) Program Grant (Acute brain injury: heterogeneity of mechanisms, therapeutic targets and outcome effects (G9439390 ID 65883)), the UK National Institute of Health Research Biomedical Research Centre at Cambridge, and the Technology Platform funding provided by the UK Department of Health. The funders had no role in study design, data collection and analyses, decision to publish, or preparation of the manuscript

Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): A Prospective Longitudinal Observational Study

BACKGROUND: Current classification of traumatic brain injury (TBI) is suboptimal, and management is based on weak evidence, with little attempt to personalize treatment. A need exists for new precision medicine and stratified management approaches that incorporate emerging technologies. OBJECTIVE: To improve characterization and classification of TBI and to identify best clinical care, using comparative effectiveness research approaches. METHODS: This multicenter, longitudinal, prospective, observational study in 22 countries across Europe and Israel will collect detailed data from 5400 consenting patients, presenting within 24 hours of injury, with a clinical diagnosis of TBI and an indication for computed tomography. Broader registry-level data collection in approximately 20 000 patients will assess generalizability. Cross sectional comprehensive outcome assessments, including quality of life and neuropsychological testing, will be performed at 6 months. Longitudinal assessments will continue up to 24 months post TBI in patient subsets. Advanced neuroimaging and genomic and biomarker data will be used to improve characterization, and analyses will include neuroinformatics approaches to address variations in process and clinical care. Results will be integrated with living systematic reviews in a process of knowledge transfer. The study initiation was from October to December 2014, and the recruitment period was for 18 to 24 months. EXPECTED OUTCOMES: Collaborative European NeuroTrauma Effectiveness Research in TBI should provide novel multidimensional approaches to TBI characterization and classification, evidence to support treatment recommendations, and benchmarks for quality of care. Data and sample repositories will ensure opportunities for legacy research. DISCUSSION: Comparative effectiveness research provides an alternative to reductionistic clinical trials in restricted patient populations by exploiting differences in biology, care, and outcome to support optimal personalized patient management

A pilot study comparing the DuoFertility&reg; monitor with ultrasound in infertile women

Jennie CB Rollason,1 Joanne G Outtrim,2 Raj S Mathur1 1Cambridge IVF, Addenbrooke&#39;s NHS Trust, 2University Division of Anaesthesia, University of Cambridge, Addenbrooke&#39;s Hospital, Cambridge, UK Background: The purpose of this study was to assess the accuracy of ovulation detection by the DuoFertility&reg; monitor compared with transvaginal ultrasound in infertile women with regular menstrual cycles. Methods: Eight infertile patients, aged 27&ndash;40 years, with a body mass index of 19&ndash;29, regular menses, normal ovaries on pelvic ultrasound scan, and normal early follicular luteinizing hormone (LH), follicle-stimulating hormone, and prolactin were recruited from infertility clinics in primary and secondary care for this pilot, prospective, observational study. The patients were asked to use the DuoFertility monitor for the whole cycle, with investigators and patients blind to DuoFertility data. Daily urine LH monitoring commenced on cycle day 8, with daily transvaginal ultrasound following the first positive LH until ovulation was observed. Ovulation was further confirmed by serum progesterone. The main outcome measure was detection of ovulation by the DuoFertility monitor, and correlation between day of ovulation assessed by DuoFertility and ultrasound. Results: DuoFertility identified ovulation as having occurred within one day of that determined via ultrasound in all cycles. The sensitivity of ovulation detection was 100% (95% confidence interval 82&ndash;100). The specificity could not be concluded from the data. Conclusion: In infertile women with regular cycles, the DuoFertility monitor appears to accurately identify ovulatory cycles and the day of ovulation. Keywords: fertility monitor, ovulation, infertility, ultrasound scan, urinary luteinizing hormon

Neural correlates of visual memory in patients with diffuse axonal injury

$\textit{Primary objective:}$ 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. $\textit{Methods and procedures:}$ 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. $\textit{Main outcomes and results:}$ 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. $\textit{Conclusions:}$ 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.This study involved secondary analysis of data collected by other studies, including the MRC collaborative Grant and TBICare. L.M.L. was funded by the Division of Anaesthesia, University of Cambridge. A.M. is supported by CLAHRC-East of England awards. E.L.C., J.G.O., J.P.C. and D.K.M. are funded by the Neuroscience Theme of the NIHR Cambridge Biomedical Research Centre and NIHR and by Framework Program 7 funding from the European Commission (CENTER-TBI). B.J.S. consults for Cambridge Cognition, Otsuka, Servier and Lundbeck. She holds a grant from Janssen/J&J and has share options in Cambridge Cognition. D.K.M also received lecture and consultancy fees and support for research from Glaxo SmithKline, Solvay and Linde. E.A.S. is funded by the Stephen Erskine Fellowship, Queens’ College, Cambridge, UK. V.F.J.N. is supported by a Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship

Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 as Outcome Predictors in Traumatic Brain Injury.

OBJECTIVE: Biomarkers ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) may help detect brain injury, assess its severity, and improve outcome prediction. This study aimed to evaluate the prognostic value of these biomarkers during the first days after brain injury. METHODS: Serum UCH-L1 and GFAP were measured in 324 patients with traumatic brain injury (TBI) enrolled in a prospective study. The outcome was assessed using the Glasgow Outcome Scale (GOS) or the extended version, Glasgow Outcome Scale-Extended (GOSE). RESULTS: Patients with full recovery had lower UCH-L1 concentrations on the second day and patients with favorable outcome had lower UCH-L1 concentrations during the first 2 days compared with patients with incomplete recovery and unfavorable outcome. Patients with full recovery and favorable outcome had significantly lower GFAP concentrations in the first 2 days than patients with incomplete recovery or unfavorable outcome. There was a strong negative correlation between outcome and UCH-L1 in the first 3 days and GFAP levels in the first 2 days. On arrival, both UCH-L1 and GFAP distinguished patients with GOS score 1-3 from patients with GOS score 4-5, but not patients with GOSE score 8 from patients with GOSE score 1-7. For UCH-L1 and GFAP to predict unfavorable outcome (GOS score ≤ 3), the area under the receiver operating characteristic curve was 0.727, and 0.723, respectively. Neither UCHL-1 nor GFAP was independently able to predict the outcome when age, worst Glasgow Coma Scale score, pupil reactivity, Injury Severity Score, and Marshall score were added into the multivariate logistic regression model. CONCLUSIONS: GFAP and UCH-L1 are significantly associated with outcome, but they do not add predictive power to commonly used prognostic variables in a population of patients with TBI of varying severities.This work was partially funded by the European Commission under the 7th Framework Programme (FP7-270259-TBIcare), the United Kingdom National Institute of Health Research Biomedical Research Centre at Cambridge, and a personal EVO grant (R.S.K.T.) from Hospital District of South-West Finland. V.F.N. is supported by a Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship. J.O., J.P.C., P.H., and D.K.M. were supported by the United Kingdom National Institute of Health Research Biomedical Research Centre at Cambridge, and D.K.M. was also supported by a Senior Investigator Award from the United Kingdom National Institute of Health Research

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

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

Background. Preliminary evidence has highlighted a likely 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 (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 an 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) than expected given the 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. 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

Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity

COVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, 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 severe COVID-19 more broadly. We sought to investigate 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 including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray. During hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens. Furthermore, a distinct process characterised 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 in the same manner as NfL and GFAP

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 hospitalisation, 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 characterised 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