Repurposing Low-Cost Consumer Technology for Motion Correction in Dementia Neuroimaging

Advances in human brain imaging are now about to make it possible to measure the two key biochemical processes involved in dementia. The central underlying biochemistry of dementia involves the accumulation of two misfolded proteins amyloid beta (Ab) and hyperphosphorylated tau (tau) in the brain. Using the clinical imaging technique Positron Emission Tomography (PET) and specific radiolabelled tracers that bind to these proteins it is possible to measure their concentration in the human brain.

This promises to allow us to better understand the disease process and in addition it provides us with the opportunity to use them in clinical trials to test the effectiveness of new therapies that are currently being developed by the pharmaceutical industry. To date, clinical trials have suffered from the problem that clinical assessment is an insufficiently accurate predictor of the disease time course. Further, it is believed that in order to intervene successfully in the disease one will have to treat subjects early when clinical measures do not provide a signal.

Thus, it is imperative to develop biomarkers that are able to i) identify subjects early on in the clinically silent phase of the disease so that they can be enrolled into clinical trials (Stratification) and ii) accurately measure changes in the brain of Ab and tau so that these can be used as measures of whether a therapy is impacting the disease time course (Therapy Monitoring).

Given the opportunities offered by misfolded protein imaging, the UK Dementia Platform initiative is proposing to establish a UK wide network of PET/MR imaging capabilities for early and differential diagnosis of neuro-degenerative pathology enabling improved risk-stratification, targeted hypothesis testing and more efficient early phase clinical trials.

However, currently the acquisition of imaging data is limited by subject motion during the period of scanning. This has the effect of degrading the quality of the images introducing errors that mean the scans may invalidated or at best reduce their accuracy and power to determine the levels of the misfolded protein concentrations. The consequence of this is that scans are wasted or the information obtained from them is reduced.

Our proposal will address this by using the low cost consumer technology (Xbox Kinect sensor) to measure the position of the subject continuously during the scanning period based on the measurement of the head position. Mathematical algorithms are then employed to reposition the data prior to reconstruction of the PET image of misfolded proteins. This enables the generation of an image that is equivalent to one that would have been obtained had the subject not moved.

We will implement our hardware and software solution to this problem and make it available to the UK dementia platform which will perform a range of imaging studies in pursuit of improved diagnosis and treatment for dementia.

We will acquire Clinical data validation packages in both the PET and MRI environment that demonstrate the value of the technology. We will show that it is accurate, easy to use and can be easily implemented in a standard clinical imaging environment.

This data will provide confidence for us to engage with Scanner manufacturers to discuss future licensing arrangements and standard incorporation into their commercial scanners.

Subject motion has long been recognised as a limiting factor in many medical imaging procedures, and remains an unsolved problem, producing inaccurate data that impacts on costs and effective diagnosis/treatment. This is particularly so for the latest generation of scanners whose intrinsic resolution exceeds the ability of patients to remain still, for example in neurodegenerative disorders. Algorithms to correct for motion are well established, yet the lack of effective, affordable, reliable motion tracking hardware has prevented widespread adoption in both research and clinical settings. Currently, there are no commercially available solutions and motion correction is limited to post-processing of scan data with its inherent limitations.

PET is a well-established neuroimaging research tool, becoming ever more important for dementia in the clinic and in drug development with novel tracers for amyloid and tau offering unique biochemical information. For these patient populations motion is a significant problem.

In a recent EPSRC/GSK CASE PhD, we acquired promising pilot data by repurposing a low cost mass-market consumer technology (Microsoft Kinect), coupling it with machine vision techniques to accurately measure PET head motion in real time with sub-mm accuracy providing confidence it could be developed into an effective device for the clinical environment. This is all achieved without special lighting, subject contact or attachment of markers that have compromised previous efforts. We have recently obtained evidence that this hardware will also work within an MRI scanning environment.

More work is required to optimise, evaluate and commercialise our applications. We will work with Imanova, with access to key expertise, to develop the technology for PET and PET/MR research imaging in neurodegeneration where it will provide an immediate impact in particular for the new MRC Dementia Platform (http://dementiasplatform.uk).

This proposal aims to develop methods to improve the quality and accuracy of noninvasive imaging of misfolded proteins in the brain for diagnosis, stratification and treatment monitoring in clinical trials of dementia therapies.

In December 2013 the UK government hosted a summit as part of its presidency of the G8 to discuss the impending crisis for health care systems posed by dementia, and more importantly, to establish plans to mitigate this crisis. Of all possible mitigation strategies the one with most sustainable outcomes would be an intervention for prevention of the disease. Many approaches are under investigation but the one with considerable promise is secondary prevention using small molecules or biologics given in the pre-clinical phase of neurodegenerative diseases such as, but not limited to, Alzheimer's disease (AD).

Who will benefit from the proposed research?
1. Imaging Centers (Academic and NHS)
2. UK Dementia Platform
3. Scanner Vendors
4. Pharmaceutical industry who are trying to develop new medicines to meet the enormous healthcare challenge of dementia.
5. Dementia patients themselves as well as their relatives and carers. In addition, clinicians and nurses involved in the care of these patients as well as charities promoting dementia will benefit.

Other beneficiaries of this work include researchers in medicine, life science, mathematical and computer science. Finally, governments and organisations who are facing the future economic crisis resulting from the increased incidence of dementia in the ageing population will benefit.

How will they benefit?
Improved imaging techniques that will provide an increase in quality of imaging data, reduction in the numbers of invalidated scans and associated costs savings. Scanner vendors will benefit from increased performance of their systems and competitive advantage over rival manufacturers. Currently there are no effective treatments for dementia. The diagnosis of dementia itself will be of little value without the development of effective therapies, thus it is the development of techniques that will enable the stratification of subjects and the measurement of sensitive endpoints in clinical trials that is essential. The development of improved imaging methods that will provide more sensitive imaging biomarkers for clinical trials will have a tremendous impact on the pharmaceutical industry which recognises from the sobering recent experience in trials that clinical assessment is an insufficiently accurate or sensitive predictor of the pathology. Further, the necessity to identify subjects who are in the preclinical phase of the disease where therapies will have the greatest impact is imperative.

Imaging misfolded proteins with PET will form a major component of the proposed UK Dementia Platform that will establish a UK wide network of facilities for early and differential diagnosis of neuro-degenerative pathology enabling improved risk-stratification, targeted hypothesis testing and more efficient early phase clinical trials. The development of more accurate imaging techniques will be essential for realizing UKDP's potential and providing pharma with the vehicle they need to efficiently investigate novel therapies.

Patients, carers, clinicians, nurses, healthcare systems and governments will all benefit from the development of effective therapies that will reduce the impact of the disease on the patient and the burden on society and healthcare costs. Sensitive noninvasive imaging biomarkers for dementia pathology will provide researchers with better tools to understand the disease process itself. A better understanding of the evolution of the key pathological hallmarks of the disease may offer insights into new therapeutic opportunities. Finally, the research will strengthen the international position of UK Life Sciences in the area of clinical trials and pharmaceutical development.