Project BIO-AX-TBI: Developing and Validating Blood and Imaging Biomarkers of Axonal Injury Following Traumatic Brain Injury
Traumatic brain injury (TBI) occurs when there is physical damage to the brain (e.g. following a car accident) and its implications are quite varied. Difficulties in clinically measuring the effects of TBI and the amount of damage that occurred in the connections between the nerve cells (axonal injury) lead to the inability to predict the outcome of TBI patients and to decide on the optimal treatment for them. It has long been known that damage to the axons in deep white matter connecting tracts is important in determining the clinical outcomes after TBI, but good tools to measure this were lacking. The aim of the BIO-AX-TBI consortium has been to find applicable ways to measure axonal injury, such as ultrasensitive blood tests, which would enable guiding treatment choices and predicting the recovery of TBI patients.
The BIO-AX-TBI consortium has brought together a multi-national team that includes members who have been working on different aspects of this problem for many years. The consortium was coordinated by David Sharp from the UK and included Henrik Zetterberg from the UK, Mauro Oddo from Switzerland, and Guido Bertolini and Sandra Magnoni from Italy.
In a recent paper, published collaboratively by all the consortium partners in the journal Science Translational Medicine, Graham et al. conducted a clinical study comparing new ultrasensitive blood tests to advanced brain imaging measures of axonal injury in order to assess whether these blood tests accurately measure brain changes and predict long-term recovery post-TBI. The study shows that the plasma concentration of the neurofilament light (NfL) protein increases in patients following TBI and correlates with a magnetic resonance imaging–based index of axonal damage. Plasma NfL concentration predicted white matter damage, as well as the clinical outcome, and testing a group of patients who had traumatic injuries, but not to the nervous system, showed good clinical specificity of NfL in TBI. Furthermore, invasive cerebral microdialysis used to measure biomarker changes deep within the white matter of the brain, showed that levels of markers such as NfL in the brain correlated very closely with blood concentrations. The results presented in this research paper indicate that measuring plasma NfL could improve diagnosis and prognosis for patients with TBI.
According to Neil Graham, one of the leaders of the research, blood biomarkers of injury are likely to transform the acute assessment of injury since they provide a much more precise means of defining what happened to the brain, compared with conventional imaging or clinical measures such as loss of consciousness or post-traumatic amnesia duration. He adds that there is a large amount of evidence to suggest that these new injury markers, such as plasma NfL, can assist in the diagnosis of axonal injury and prognostication, therefore efforts are now underway to deliver these to clinicians and make them available within UK hospitals. Hoping that in the future these tests will help patients and doctors to stratify injury and ensure that interventions are targeted where needed, as well as assist in performing clinical trials of treatments to prevent the development of long-term problems, such as dementia post-TBI.
Graham further states that the NEURON funding scheme has been critical in their ability to deliver this ambitious, translational neuroscientific research. The transnational aspect of the funding scheme enabled the pooling of expertise from world-leading centres in TBI management and allowed the recruitment of large numbers of patients, who were assessed in great detail and followed up longitudinally, thus enabling drawing, with confidence, the important clinical conclusions described in the Science Translational Medicine paper.
Work of this scale, providing definitive answers to the underlying clinical and scientific questions, would not have been possible without the collaborative effort spanning the UK, Switzerland, Italy and Slovenia. We benefitted hugely from the complementary expertise and perspectives of expert colleagues across Europe.
For reference: Graham NSN, Zimmerman KA, Moro F, Heslegrave A, Maillard SA, Bernini A, Miroz JP, Donat CK, Lopez MY, Bourke N, Jolly AE, Mallas EJ, Soreq E, Wilson MH, Fatania G, Roi D, Patel MC, Garbero E, Nattino G, Baciu C, Fainardi E, Chieregato A, Gradisek P, Magnoni S, Oddo M, Zetterberg H, Bertolini G, Sharp DJ. Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury. Sci Transl Med. 2021 Sep 29;13(613):eabg9922. doi: 10.1126/scitranslmed.abg9922. Epub 2021 Sep 29. PMID: 34586833.
MESCOG (‘Mechanisms of small vessel related brain damage and cognitive impairment: integrating imaging findings from genetic and sporadic disease‘)
REVIS ('Restoration of Vision after Stroke'): development of treatment for people with loss of vision
The international research project was funded under the framework of the ERA-NET NEURON.
A Neuron 2012 paper on research funded under the frame of ERA-NET NEURON
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