Developing and validating blood and imaging BIOmarkers of AXonal injury following Traumatic Brain Injury

Traumatic brain injury (TBI) occurs when the brain is physically damaged, for example after a car crash. It is common and survivors often have major on-going problems. It is very difficult to predict how patients will do after TBI. One reason for this is that we are unable to measure all the effects of TBI. An important factor is that the connections between nerve cells are damaged by the impact on the brain of an injury (axonal injury). This damage has been difficult to measure in the past, but new ways to scan the brain and more sensitive ways of picking up the effects of this injury in the blood could change this. In other parts of medicine tests of this type have had a dramatic effect on how we treat patients. For example, the products of heart muscle damage that have leaked into the blood can be used identify a heart attack and guide treatment. We need similar tests to be available in TBI. This should be possible as the products of axonal injury also leak into the blood and we have a sensitive way to pick this up. An accurate test for axonal injury would guide treatment choices and allow us to predict how patients will recover. We have brought together an international team who have been working on different aspects of this problem for many years. Together we will conduct a large study to identify the best measures of axonal injury. We will carefully test whether these measures help us predict outcomes and will study where the blood markers come from using a safe method to measure the effects of axonal injury directly from the brain. The work links into some large projects that have already started and will use a standard way to assess patients after their injury. This is important because it will allow us to share results across studies. We hope the work will allow us to identify a blood marker for TBI that could be widely used to quickly identify the presence of axonal injury. We will also show what brain imaging measure is best at picking up axonal injury and how best to combine the measures to best predict how patients recover. This will allow doctors to diagnose problems after TBI more accurately, choose the right treatments and give patients and their families accurate advice about what will happen after discharge from hospital.

Outcomes after traumatic brain injury (TBI) remain hard to predict. This is partly because axonal injury, which is of fundamental importance, is difficult to measure clinically. Advances in magnetic resonance imaging (MRI) now allow axonal injury to be sensitively detected after TBI. Fluid biomarkers provide a complementary measure, as cytoskeletal proteins are released from damaged axons. We will perform a multicenter study of adult TBI investigating the relationship between plasma, microdialysis and neuroimaging markers of axonal injury. An advanced bioinformatics will be used across the difference parts of the study, building on the CREATIVE system for integrated collection of multi-dimensional clinical data. We will test the relationship between the most promising fluid biomarkers, in particular neurofilament light (NFL) and tau protein, and MRI measures of axonal injury including diffusion MRI (N=250). Longitudinal neuroimaging and blood biomarker data will be collected, allowing us to assess biomarker dynamics their relation to neurodegeneration measured by brain atrophy. A subgroup of patients will be assessed using microdialysis (N=40), which will allow local production of NFL and tau to be investigated. Biomarkers most closely linked to outcome will be identified from our first cohort (N=250) using logistic regression to model mortality and clinical outcome. These results will be validated using a larger cohort of patients from CREACTIVE (N=~1000), where we will also investigate the diagnostic utility of CT head imaging. The project will allow us to: (a) cross validate in vivo methods for assessing axonal injury following TBI; (b) test whether combining measures of axonal injury provides improved diagnostic and prognostic information; (c) gain insights about the underlying mechanisms of axonal injury.

If successful the work we propose will provide the robust blood and neuroimaging measures of axonal injury and disease progression after TBI. This will have impact in a number of areas:

(a) Health Care Professionals
The availability of neuroimaging and plasma biomarkers for axonal injury will facilitate early diagnosis of axonal injury and improve prognostication after TBI. This has the potential to have very significant impact on TBI care as specific tests for axonal injury are not currently available clinically. By validating the value of these biomarkers in a carefully controlled analysis of clinical outcome we will provide strong evidence for their clinical use.

(b) Patients & Families
The research will improve quality of life and health of TBI patients. There is often great uncertainty about clinical outcome after TBI. This creates problems for patients and their families and often leads to inappropriate treatment or the lack of treatment. For example, the presence of significant axonal injury can easily be missed using current diagnostic approaches. This results in a failure of patients and their families to appreciate the significance of an injury. By providing more accurate diagnosis we will assist patients and their families in adapting to life after their injury.

(c) Research & pharma impact: patient stratification
The major challenge for therapeutic research in TBI is the large heterogeneity of pathology produced by the injury. This results in highly variable trajectories of recovery and means that clinical trials in unselected patient groups either need to very large (e.g. N>20000) or risk being underpowered. An important way of improving clinical trails of new treatments for axonal injury is to: (a) stratify patient entry into trials on the basis of biomarker evidence of axonal injury; and (b) use validated biomarkers as outcome measures. Our research will deliver these biomarkers, which researchers and pharma can confidently use because they are are validated against clinical outcomes in a large population. This will have a major effect on the feasibility of work in the area. For example, our power calculations indicate that if our observed white matter atrophy rates of 1.5% per year are used as a biomarker of progressive axonal injury, a clinical trial with N=150 patients in each arm would be powered to detect a 25% slowing of atrophy with 80% confidence.

(d) Financial
The total cost of TBI in Europe was estimated to be E33 billion in 2010 (30). Hence, even small improvements in the diagnostic accuracy or treatment efficacy of TBI-related axonal injury will yield dramatic short and long-term financial benefits. Improving the ability to predict clinical outcome will improve the selection of treaments and allow efficient planning of patient rehabilitation. We expect this to produce significant economic savings if implemented widely.

(e) Policy impact
Clarifying the numbers of patients with axonal injury and their likely clinical outcomes will impact on healthcare policy by providing accurate information about prognosis in subgroups of TBI patients.