MICA: Assessing tau levels after traumatic brain injury (TBI) using [18F]T807 positron emission tomography (PET)

Traumatic Brain Injury (TBI) happens when the brain is damaged by physical injury, for example, after a car crash, a fall or a sporting injury. It is very common, and patients who have TBI often have long-term disabilities that have far-reaching consequences, such as job-loss or relationship breakdown. We currently do not have good treatments for these long-term problems, or even accurate ways of predicting whether they might occur.

The long-term outcome after TBI is actually very unpredictable, and many patients do surprisingly badly. A large study in Glasgow has followed-up patients since their injuries in 1995. At the time of the last assessment about 40% had died, and of the ones who survived many had continued to deteriorate long after their injuries. The reasons for this are unclear, but there is growing evidence that TBI can trigger the kind of gradual death of brain cells that is characteristic of conditions like Alzheimer's Disease. In fact, a significant head injury makes it much more likely that you will develop Alzheimer's Disease many years later.

One characteristic feature of Alzheimer's Disease and other types of dementia is the presence of an abnormal type of a protein called tau. The protein forms clumps or 'tangles' in affected brain cells, and this is thought to be an important factor in the death or 'neurodegeneration' of these brain cells. Abnormalities of tau are also seen following TBI, and this provides an obvious link between a head injury and neurodegeneration that occurs many years later. The problem has been that it is very difficult to identify and study tau pathology without having brain tissue to look at under the microscope. What is needed is a way of testing for the presence of abnormal tau protein, without patients needing to have an operation.

A brain imaging technique called positron emission tomography (PET) provides a potential solution to the problem. Early studies show that a particular type of PET can be used to demonstrate tau abnormalities. The method has been successfully used in patients with Alzheimer's Disease, and this opens the exciting possibility that PET could be used to test for abnormal tau in other neurological conditions such as TBI.

We proposed investigating whether PET can be used to identify abnormal tau following TBI. The project is a collaboration between a number of research and commercial groups who have complementary expertise. We will investigate the group of patients from Glasgow who have already been shown to have extremely variable outcome, and who have had detailed follow up for many years. In addition to PET scanning, patients will have detailed clinical and psychological testing, as well as another type of brain scanning (MRI) that allows the amount of brain injury after TBI to be determined. We will test whether patients who have done badly after their injuries have high levels of abnormal tau protein, and whether this is associated with particular patterns of brain injury and psychological problems.

This will be first time this work has been attempted in TBI. We hope the work will allow us to identify patients with evidence of neurodegeneration, who are at risk of psychological problems, dementia and early death. Ultimately this will assist doctors in making an early diagnosis in TBI patients, and will allow us to more efficiently conduct trials of new treatments in groups of TBI patients who are most likely to benefit from them.

The long-term effects of traumatic brain injury (TBI) are often devastating and under-recognised. This has resulted in a 'silent epidemic' of disability, with enormous social and economic costs. In a unique patient cohort from Glasgow, the cumulative mortality rate 13 years after all types of head injury was more than 40%. Patients who survive, often develop catastrophic social problems. A major factor driving disability is the development of neurodegeneration. A key pathological marker of this is the accumulation of abnormal tau protein. TBI patients are at risk of both Alzheimer's disease (AD) and chronic traumatic encephalopathy, with neurofibrillary tangles containing hyperphosphorylated tau present in both diseases. There is a pressing clinical need for in vivo tau neuroimaging as this would allow patients to be stratified using a key marker of the early stages of neurodegeneration after TBI.

In collaboration with Imanova and AVID, we will investigate the utility of [18F]T807 as a tool to investigate tau pathology following TBI. We will test the hypothesis that patients with long-term disabilities after TBI have high levels of abnormal tau as measured by [18F]T807 PET. Patients will be recruited from the Glasgow cohort who have continuously followed-up since head injuries in 1995/6. The trajectory of clinical outcome has been tracked, allowing an accurate assessment of its relationship to tau pathology. Advanced MRI techniques will also be used to assess structural and functional measures of neurodegeneration, and these will correlated with the level of tau pathology. If successful this work will: (a) provide a sensitive and specific marker of tau pathology after TBI, which will allow us to stratify patients for risk of accelerated cognitive decline and dementia; and (b) provide support for the use of [18F]T807 PET as a diagnostic tool for the identification of neurodegeneration after TBI.

If successful the work we propose will provide a sensitive and specific marker of tau pathology after TBI. This would have impact across a number of areas:

(1) Health Care Professionals
Patients often present to clinicians with progressive cognitive and psychiatric problems after TBI, but it is currently difficult to evaluate their underlying cause. We have no specific diagnostic tools for identifying the presence of progressive neurodegeneration after TBI. The work would provide a proof-of-principle that tau imaging can be used to identify patients at risk of early dementia after TBI. The availability of this type of diagnostic tool would greatly enhance the ability of neurologists and psychiatrists to identify the underlying mechanism for late decline after TBI, allowing them to plan early social and medical interventions in those patients at risk of developing dementia.

(2) Patients & Families
The research has the potential to improve quality of life and health of TBI patients. There is great uncertainty about the reasons for varying clinical outcome after TBI. This creates problems for patients and their families. For example, we have been investigating the causes of poor long-term outcome after blast TBI in soldiers returning from service in Afghanistan (1). Conventional approaches, including standard MRI assessment, often fail to identify an underlying organic cause for persistent problems. This creates major confusion, and sometimes leads to inappropriate treatment. Blast TBI has been shown to lead to tau pathology (2), and the ability to identify this in vivo would help clarify the cause of on-going impairments. This would allow patients and their families to plan appropriately for the future, as well as avoiding the stigmatizing effects that psychiatric diagnoses might have.

(3) Pharma impact: patient stratification
Our work also has the potential to increase the economic competitiveness of UK based pharmaceutical companies. A major benefit would be the ability to identify TBI patients at risk of neurodegeneration. This would allow patients to be selected early for interventions intended to modify disease course as they become available. Large investments are being made in trials to develop drugs to limit the progression of neurodegeneration. These would have a greater impact if they were targeted appropriately. The use of [18F]T807 PET to stratify TBI patients would be able accelerate the development of such interventions, by enabling smaller, faster trials in this high-risk population.

(4) Financial
The long-term indirect costs of TBI are around £4 billion/year (3). Therefore, even small improvements in the diagnostic accuracy or treatment efficacy of TBI could yield dramatic financial benefits. Our ultimate goal is to be able of employ disease modifying therapy early after TBI to slow or prevent the development of dementia. Success in this long-term goal, this would obviously yield dramatic long-term financial benefits. In the shorter-term, improvements in diagnostic accuracy could yield financial savings, as the clinical uncertainty that accompanies these patients results in them having large numbers of healthcare consultations and investigations, that could be reduced with early accurate diagnosis.

(5) Policy impact
The work of the Glasgow research team over the last 25 years has highlighted the dire long-term consequences of TBI for many patients. However, compared to other conditions of equivalent societal impact there is a lack of research and healthcare focus in this area. This work will emphasise the link between TBI and dementia, and will provide impetus for a chance in healthcare policy towards this neglected group of patients.

References
(1) Baxter D, et al. (2013) Ann Neurol. (In Press).
(2) Goldstein LE, et al. (2012) Sci Trans Med 4:134.
(3) Gustavsson A, et al. (2011) Europ Neuropsychopharm 21:718-779.