Non-Invasive Imaging of Glymphatic Clearance: A Novel Strategy for the Early Diagnosis of Alzheimer's Disease

Alzheimer's disease is a devastating illness that causes severe memory loss. Despite the huge social, economic and emotional burden of the condition, there is currently no cure. The development of effective treatments is hindered by the difficulty of accurately identifying the early phase of the disease, years before symptoms become apparent.

Recent evidence has come to light of a previously unrecognised waste removal system that clears excess fluid and toxins from the brain. It is thought that impairment of this pathway, known as the glymphatic system, may be a critical causal factor in the development of Alzheimer's disease. However, currently this pathway cannot be measured in humans.

We will develop the first non-invasive methods to image the glymphatic system using MRI, enabling assessment in the human brain for the first time. The new techniques will be carefully assessed by: i) comparison to existing invasive methods that require the injection of imaging agents into the fluid that surrounds the brain, ii) imaging mouse models of impaired glymphatic clearance and comparison with healthy mice.

Taken together, this proposal may lead to a new method for early detection of Alzheimer's disease and identify a new target for effective treatment.

The work set out in this proposal has the potential to provide a breakthrough in the early diagnosis of AD. The successful development of the technology may lead to widespread clinical application for patient stratification in the early stages of AD pathogenesis. The ability to accurately identify patients at risk of developing AD may markedly increase the efficacy of emerging treatments to delay or prevent clinical symptoms. By developing a new diagnostic tool using novel MRI sequences, we will help alleviate the burden of this oppressive and prevalent condition within society.

Benefit to the patient: Despite the medical care costs of Alzheimer's disease equalling that of cancer and heart disease combined in the UK, there is currently no cure. There is a clear consensus from the AD research community, however, that if upstream disease processes can be accurately identified, then early interventional treatments may delay or prevent clinical symptoms. A successful clinical strategy for the early diagnosis and treatment of AD would have a hugely beneficial impact on patients by lessening the devastating symptoms (memory loss, cognitive impairment) associated with later stages of disease, which is ultimately fatal.

Benefit to Industry: The successful development and validation of the novel, non-invasive and translatable techniques to assess glymphatic function, may each represent a patentable technology. At the earliest opportunity we will seek to protect the intellectual property that will arise during the course of this program of work in conjunction with UCL and the EPSRC. The successful clinical translation of the MRI techniques for the accurate early staging of AD would then represent a highly valuable technology for hospitals and their industrial partners (e.g Siemens, Philips, GE) around the world. In addition, accurate staging of the disease for patient stratification would provide crucial information for pharmaceutical companies in the drive to uncover effective treatments for the condition, where the efficacy of new drugs may be highly dependent on the time-point of therapeutic intervention within the AD cascade.

Awareness of the public: Industry-academic partnerships in imaging in neurodegenerative disease will increase in the coming years, and public understanding and support will be needed to maximise chances of success. We believe it is vital that scientific breakthrough is communicated to the general public and that the dissemination of these complex ideas is done in a non-reductive, yet accessible way. CABI has led several high profile public engagement programs in recent years including Imaging at the Royal Society and at the Cheltenham Science festival. We will continue to prioritise approaches to improve the public perception of the value of the novel technologies to be developed in this proposal for improved AD diagnosis and successful treatment development.

Collaboration and Capability: This is a collaborative proposal between the UCL Centre for Advanced Biomedical Imaging (Mark Lythgoe), the UCL Centre for Neurodegenerative disease (Elizabeth Fisher), Michael O'Neill (Head of Molecular Pathology, Eli Lilly) and the Leonard Wolfson Experimental Neurology Centre (David Thomas, Nick Fox). This will strengthen existing ties between the centres and provide a translational platform for the new technologies, developed in this proposal.