Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study.

BACKGROUND: Traumatic brain injury (TBI) is common in military campaigns and is a risk factor for dementia. ArmeD SerVices TrAuma and RehabilitatioN OutComE-TBI (ADVANCE-TBI) aims to ascertain neurological outcomes in UK military personnel with major battlefield trauma, leveraging advances in quantification of axonal breakdown markers like neurofilament light (NfL), and astroglial marker glial fibrillar acidic protein (GFAP) in blood. We aimed to describe the causes, prevalence and consequences of TBI, and its fluid biomarker associations. METHODS: TBI history was ascertained in 1145 servicemen and veterans, of whom 579 had been exposed to major trauma. Functional and mental health assessments were administered, and blood samples were collected approximately 8 years postinjury, with plasma biomarkers quantified (n=1125) for NfL, GFAP, total tau, phospho-tau181, amyloid-ß 42 and 40. Outcomes were related to neurotrauma exposure. RESULTS: TBI was present in 16.9% (n=98) of exposed participants, with 46.9% classified as mild-probable and 53.1% classified as moderate to severe. Depression (ß=1.65, 95% CI (1.33 to 2.03)), anxiety (ß=1.65 (1.34 to 2.03)) and post-traumatic stress disorder (ß=1.30 (1.19 to 1.41)) symptoms were more common after TBI, alongside poorer 6 minute walk distance (ß=0.79 (0.74 to 0.84)) and quality of life (ß=1.27 (1.19 to 1.36), all p<0.001). Plasma GFAP was 11% (95% CI 2 to 21) higher post-TBI (p=0.013), with greater concentrations in moderate-to-severe injuries (47% higher than mild-probable (95% CI 20% to 82%, p<0.001). Unemployment was more common among those with elevated GFAP levels post-TBI, showing a 1.14-fold increase (95% CI 1.03 to 1.27, p<0.001) for every doubling in GFAP concentration. CONCLUSIONS: TBI affected nearly a fifth of trauma-exposed personnel, related to worse mental health, motor and functional outcomes, as well as elevated plasma GFAP levels 8 years post-injury. This was absent after extracranial trauma, and showed a dose-response relationship with the severity of the injury.

Detecting axonal injury in individual patients after traumatic brain injury.

Poor outcomes after traumatic brain injury (TBI) are common yet remain difficult to predict. Diffuse axonal injury is important for outcomes, but its assessment remains limited in the clinical setting. Currently, axonal injury is diagnosed based on clinical presentation, visible damage to the white matter or via surrogate markers of axonal injury such as microbleeds. These do not accurately quantify axonal injury leading to misdiagnosis in a proportion of patients. Diffusion tensor imaging provides a quantitative measure of axonal injury in vivo, with fractional anisotropy often used as a proxy for white matter damage. Diffusion imaging has been widely used in TBI but is not routinely applied clinically. This is in part because robust analysis methods to diagnose axonal injury at the individual level have not yet been developed. Here, we present a pipeline for diffusion imaging analysis designed to accurately assess the presence of axonal injury in large white matter tracts in individuals. Average fractional anisotropy is calculated from tracts selected on the basis of high test-retest reliability, good anatomical coverage and their association to cognitive and clinical impairments after TBI. We test our pipeline for common methodological issues such as the impact of varying control sample sizes, focal lesions and age-related changes to demonstrate high specificity, sensitivity and test-retest reliability. We assess 92 patients with moderate-severe TBI in the chronic phase (≥6 months post-injury), 25 patients in the subacute phase (10 days to 6 weeks post-injury) with 6-month follow-up and a large control cohort (n = 103). Evidence of axonal injury is identified in 52% of chronic and 28% of subacute patients. Those classified with axonal injury had significantly poorer cognitive and functional outcomes than those without, a difference not seen for focal lesions or microbleeds. Almost a third of patients with unremarkable standard MRIs had evidence of axonal injury, whilst 40% of patients with visible microbleeds had no diffusion evidence of axonal injury. More diffusion abnormality was seen with greater time since injury, across individuals at various chronic injury times and within individuals between subacute and 6-month scans. We provide evidence that this pipeline can be used to diagnose axonal injury in individual patients at subacute and chronic time points, and that diffusion MRI provides a sensitive and complementary measure when compared to susceptibility weighted imaging, which measures diffuse vascular injury. Guidelines for the implementation of this pipeline in a clinical setting are discussed.

Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging.

Cognitive impairment is common following traumatic brain injury. Dopaminergic drugs can enhance cognition after traumatic brain injury, but individual responses are highly variable. This may be due to variability in dopaminergic damage between patients. We investigate whether measuring dopamine transporter levels using 123I-ioflupane single-photon emission computed tomography (SPECT) predicts response to methylphenidate, a stimulant with dopaminergic effects. Forty patients with moderate-severe traumatic brain injury and cognitive impairments completed a randomized, double-blind, placebo-controlled, crossover study. 123I-ioflupane SPECT, MRI and neuropsychological testing were performed. Patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Subjects received neuropsychological assessment after each block and completed daily home cognitive testing during the trial. The primary outcome measure was change in choice reaction time produced by methylphenidate and its relationship to stratification of patients into groups with normal and low dopamine transporter binding in the caudate. Overall, traumatic brain injury patients showed slow information processing speed. Patients with low caudate dopamine transporter binding showed improvement in response times with methylphenidate compared to placebo [median change = -16 ms; 95% confidence interval (CI): -28 to -3 ms; P = 0.02]. This represents a 27% improvement in the slowing produced by traumatic brain injury. Patients with normal dopamine transporter binding did not improve. Daily home-based choice reaction time results supported this: the low dopamine transporter group improved (median change -19 ms; 95% CI: -23 to -7 ms; P = 0.002) with no change in the normal dopamine transporter group (P = 0.50). The low dopamine transporter group also improved on self-reported and caregiver apathy assessments (P = 0.03 and P = 0.02, respectively). Both groups reported improvements in fatigue (P = 0.03 and P = 0.007). The cognitive effects of methylphenidate after traumatic brain injury were only seen in patients with low caudate dopamine transporter levels. This shows that identifying patients with a hypodopaminergic state after traumatic brain injury can help stratify the choice of cognitive enhancing therapy.

Neuropsychological outcomes following traumatic brain injury.

This review examines the clinical and neuroradiological features of traumatic brain injury that are most frequently associated with persistent cognitive complaints. Neuropsychological outcomes do not depend solely on brain injury severity but result from a complex interplay between premorbid factors, the extent and nature of the underlying structural damage, the person's neuropsychological reserve and the impact of non-neurological factors in the recovery process. Brain injury severity is only one of these factors and has limited prognostic significance with respect to neuropsychological outcome. We examine the preinjury and postinjury factors that interact with the severity of a traumatic brain injury to shape outcome trajectories. We aim to provide a practical base on which to build discussions with the patient and their family about what to expect following injury and also to plan appropriate neurorehabilitation.

Post-traumatic amnesia and confusional state: hazards of retrospective assessment.

Retrospective assessment of post-traumatic amnesia (PTA) must take into account factors other than traumatic brain injury (TBI) which may impact on memory both at the time of injury and subsequent to the injury. These include analgesics, anaesthesia required for surgery, and the development of acute or post-traumatic stress disorder. This is relevant in clinical and medicolegal settings. Repeated assessments of the post-injury state, involving tests for continuing amnesia, risk promoting recall of events suggested by the examiner, or generating confabulations. The PTA syndrome affects the categorical autobiographical memory, and is accompanied by confusion as an essential component; this should be suspected from the initial or early Glasgow Coma Scale score (13-14/15) if not directly recorded by clinical staff. PTA by itself is only one of several indices of severity of TBI. The nature of the head injury, including observers' accounts, clinical and neuroimaging data, the possible role of other external injuries, blood loss, acute stress disorder and the potential for hypoxic brain injury, must be taken into account as well as concomitant alcohol or substance abuse, and systemic shock. A plausible mechanism for a TBI must be demonstrable, and other causes of amnesia excluded.

Smartphone technology: Gentle reminders of everyday tasks for those with prospective memory difficulties post-brain injury.

BACKGROUND: Prospective memory is a common deficit following brain injury that can reduce an individuals' ability to complete everyday tasks. The smartphone is a device that may compensate for these difficulties using the calendar's prompting function. Reminders can be programmed remotely using email to phone synchronization. OBJECTIVE: To explore whether smartphone reminders help people complete pre-identified tasks as compared to when reminders are not provided. METHODS: An ABAB case series design compared reminder present vs. reminder absent phases with regards completion of pre-set tasks. Six participants aged 24-55 with Acquired Brain Injury (ABI) and five caregivers participated in the study. Both completed a series of questionnaires looking at the impact of the smartphone reminders on everyday memory functioning at pre, post and follow-up. A 3-month follow-up questionnaire assessed continued use of the system. RESULTS: There was a significant improvement in task completion rates when smartphone reminders were provided. A thematic analysis identified that smartphone reminders improved independence, confidence in coping with memory difficulties and general mood. All participants were still using the system at 3-month follow-up. CONCLUSIONS: Smartphone reminders may provide a cost-effective, accessible and non-stigmatizing tool for participants to compensate for prospective memory difficulties.

Falls and traumatic brain injury in adults under the age of sixty.

Falls are a significant cause of traumatic brain injury (TBI). There has been little research into falls resulting in a TBI in adults under the age of 60. The authors retrospectively analysed consecutive referrals to their community rehabilitation service between 2009 and 2012 in order to determine whether falls are a common cause of TBI in adults under 60, the different types of falls, the presence of alcohol at the time of the fall, and return to work following TBI. Falls accounted for 25 % of TBI. Ground-level falls and falls down stairs were the main causes of falls leading to TBI. Alcohol was present in 30 % of the falls. 44 % of individuals who had been working prior to their fall related-TBI had returned to work 1 year post-TBI. The authors conclude that falls amongst adults under sixty is an important cause of traumatic brain injury, and requires preventative and reduction strategies.

How do experts reporting for the legal process validate symptoms? The results of a survey.

This article examines the views of experts from a range of disciplines and how they view symptoms given to them by claimants in matters of personal injury or medical negligence assessments. The survey was carried out in 2009 and looks at current practice and attitudes from a number of different disciplines. The survey included questions looking at what percentage of cases were thought to be genuine, symptoms most likely to be elaborated, methods for assessing symptom validity, and documentary evidence required for a report. This article highlights the importance of looking at symptom validation in the legal process.

Prospective cohort study of long-term neurological outcomes in retired elite athletes: the Advanced BiomaRker, Advanced Imaging and Neurocognitive (BRAIN) Health Study protocol.

INTRODUCTION: Although limited, recent research suggests that contact sport participation might have an adverse long-term effect on brain health. Further work is required to determine whether this includes an increased risk of neurodegenerative disease and/or subsequent changes in cognition and behaviour. The Advanced BiomaRker, Advanced Imaging and Neurocognitive Health Study will prospectively examine the neurological, psychiatric, psychological and general health of retired elite-level rugby union and association football/soccer players. METHODS AND ANALYSIS: 400 retired athletes will be recruited (200 rugby union and 200 association football players, male and female). Athletes will undergo a detailed clinical assessment, advanced neuroimaging, blood testing for a range of brain health outcomes and neuropsychological assessment longitudinally. Follow-up assessments will be completed at 2 and 4 years after baseline visit. 60 healthy volunteers will be recruited and undergo an aligned assessment protocol including advanced neuroimaging, blood testing and neuropsychological assessment. We will describe the previous exposure to head injuries across the cohort and investigate relationships between biomarkers of brain injury and clinical outcomes including cognitive performance, clinical diagnoses and psychiatric symptom burden. ETHICS AND DISSEMINATION: Relevant ethical approvals have been granted by the Camberwell St Giles Research Ethics Committee (Ref: 17/LO/2066). The study findings will be disseminated through manuscripts in clinical/academic journals, presentations at professional conferences and through participant and stakeholder communications.

ADVANCE-TBI study protocol: traumatic brain injury outcomes in UK military personnel serving in Afghanistan between 2003 and 2014 - a longitudinal cohort study.

INTRODUCTION: Outcomes of traumatic brain injury (TBI) are highly variable, with cognitive and psychiatric problems often present in survivors, including an increased dementia risk in the long term. Military personnel are at an increased occupational risk of TBI, with high rates of complex polytrauma including TBI characterising the UK campaign in Afghanistan. The ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE)-TBI substudy will describe the patterns, associations and long-term outcomes of TBI in the established ADVANCE cohort. METHODS AND ANALYSIS: The ADVANCE cohort comprises 579 military personnel exposed to major battlefield trauma requiring medical evacuation, and 566 matched military personnel without major trauma. TBI exposure has been captured at baseline using a standardised interview and registry data, and will be refined at first follow-up visit with the Ohio State Method TBI interview (a National Institute of Neurological Disorders and Stroke TBI common data element). Participants will undergo blood sampling, MRI and detailed neuropsychological assessment longitudinally as part of their follow-up visits every 3-5 years over a 20-year period. Biomarkers of injury, neuroinflammation and degeneration will be quantified in blood, and polygenic risk scores calculated for neurodegeneration. Age-matched healthy volunteers will be recruited as controls for MRI analyses. We will describe TBI exposure across the cohort, and consider any relationship with advanced biomarkers of injury and clinical outcomes including cognitive performance, neuropsychiatric symptom burden and function. The influence of genotype will be assessed. This research will explore the relationship between military head injury exposure and long-term outcomes, providing insights into underlying disease mechanisms and informing prevention interventions. ETHICS AND DISSEMINATION: The ADVANCE-TBI substudy has received a favourable opinion from the Ministry of Defence Research Ethics Committee (ref: 2126/MODREC/22). Findings will be disseminated via publications in peer-reviewed journals and presentations at conferences.

Computerised cognitive assessment in patients with traumatic brain injury: an observational study of feasibility and sensitivity relative to established clinical scales.

Background: Online technology could potentially revolutionise how patients are cognitively assessed and monitored. However, it remains unclear whether assessments conducted remotely can match established pen-and-paper neuropsychological tests in terms of sensitivity and specificity. Methods: This observational study aimed to optimise an online cognitive assessment for use in traumatic brain injury (TBI) clinics. The tertiary referral clinic in which this tool has been clinically implemented typically sees patients a minimum of 6 months post-injury in the chronic phase. Between March and August 2019, we conducted a cross-group, cross-device and factor analyses at the St. Mary's Hospital TBI clinic and major trauma wards at Imperial College NHS trust and St. George's Hospital in London (UK), to identify a battery of tasks that assess aspects of cognition affected by TBI. Between September 2019 and February 2020, we evaluated the online battery against standard face-to-face neuropsychological tests at the Imperial College London research centre. Canonical Correlation Analysis (CCA) determined the shared variance between the online battery and standard neuropsychological tests. Finally, between October 2020 and December 2021, the tests were integrated into a framework that automatically generates a results report where patients' performance is compared to a large normative dataset. We piloted this as a practical tool to be used under supervised and unsupervised conditions at the St. Mary's Hospital TBI clinic in London (UK). Findings: The online assessment discriminated processing-speed, visual-attention, working-memory, and executive-function deficits in TBI. CCA identified two significant modes indicating shared variance with standard neuropsychological tests (r = 0.86, p < 0.001 and r = 0.81, p = 0.02). Sensitivity to cognitive deficits after TBI was evident in the TBI clinic setting under supervised and unsupervised conditions (F (15,555) = 3.99; p < 0.001). Interpretation: Online cognitive assessment of TBI patients is feasible, sensitive, and efficient. When combined with normative sociodemographic models and autogenerated reports, it has the potential to transform cognitive assessment in the healthcare setting. Funding: This work was funded by a National Institute for Health Research (NIHR) Invention for Innovation (i4i) grant awarded to DJS and AH (II-LB-0715-20006).

Underemployment: consequences for the health and well-being of workers.

This paper addresses the question of how the adequacy of a person's employment status influences their health. We draw on and extend the Labor Utilization Framework to distinguish between different forms of underemployment (hours, income, skills, and status) and test their relative effects on a range of physical health and psychological well-being outcomes. Using data drawn from a nationally representative sample (N = 1,429) of adults of working age, we assess the concurrent effects of underemployment through a longitudinal design that controls for prior levels of health and well-being. The results indicate that underemployed workers do report lower levels of health and well-being than adequately employed workers. However, the relationship varies by both types of underemployment and indicator of health and well-being. We conclude by discussing future research to explore the relationship between underemployment and health and well-being.